Tuberculosis

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Pathophysiology

7

Phagocytosis

Mycobacterium tuberculosis is engulfed by alveolar macrophages but resists destruction, leading to granuloma formation.

Macrophage CL:0000235 T Cell CL:0000084 neutrophil CL:0000775 dendritic cell CL:0000451

type I interferon signaling pathway GO:0060337 autophagy GO:0006914 phagosome maturation GO:0090382

Experimental models

Autologous iPSC-derived alveolus-on-chip (iLoC) Mtb infection model ORGAN ON CHIP Alveolar macrophages and epithelial cells take up Mtb, reproducing the initial uptake step in a human alveolar microenvironment.

Downstream

GBP4-Mediated Autophagy-Dependent TB Restriction Phagocytosis of M. tuberculosis triggers type I interferon signaling, which induces GBP4 expression as a host-directed restriction mechanism.

Granuloma Formation Infected macrophages differentiate into foamy macrophages which form the cellular core of TB granulomas.

Show evidence (4 references)

PMID:14745511 SUPPORT

"The immune response to Mycobacterium tuberculosis (Mtb) infection is the formation of multicellular lesions, or granolomas, in the lung of the individual"

This reference supports the claim that Mycobacterium tuberculosis infection leads to granuloma formation.

PMID:30306257 SUPPORT

"Phagocytosis refers to the process of internalization and degradation of particulate material... One microbe that is particularly successful at surviving within macrophages is the pathogen Mycobacterium tuberculosis, which can efficiently manipulate the macrophage at several levels, including..."

This reference supports the specific involvement of macrophages and the resistance of Mycobacterium tuberculosis to degradation within phagocytes.

PMID:2425678 SUPPORT

"The process of granuloma formation in the lung is mediated by an intimate interaction between macrophages and T cells, and this interaction provides the appropriate environment for granuloma formation and the development of fibrosis."

While this reference supports the role of macrophages and T cells in granuloma formation, it does not address the specific mechanisms by which Mycobacterium tuberculosis resists destruction.

+ 1 more reference

GBP4-Mediated Autophagy-Dependent TB Restriction

Type I interferon-inducible GBP4 (guanylate-binding protein 4) mediates autophagy-dependent restriction of Mycobacterium tuberculosis through a TRIM21-dependent autophagy pathway that prevents SORT1-mediated progranulin degradation. This activates TFEB and FOXO3a, driving lysosomal acidification and phagosome-lysosome fusion to enhance intracellular bacterial killing.

Macrophage CL:0000235

type I interferon signaling pathway GO:0060337 ↑ INCREASED autophagy GO:0006914 ↑ INCREASED phagosome maturation GO:0090382 ↑ INCREASED

Experimental models

Autologous iPSC-derived alveolus-on-chip (iLoC) Mtb infection model ORGAN ON CHIP A macrophage-restricted ATG14 knockout tests the autophagy requirement directly. The result refines the usual framing: ATG14 loss raised macrophage necrosis without permitting bacterial replication, separating autophagy's role in host-cell survival from its role in bacterial restriction.

Show evidence (1 reference)

PMID:42501331 SUPPORT In Vitro

"Our study uncovers a key role for GBP4 in regulating cell-autonomous resistance in human macrophages and may facilitate the development of host-directed therapies against tuberculosis"

This study characterizes GBP4 as a type I IFN-inducible host factor specifically mediating autophagy-dependent TB restriction in human macrophages, a previously incompletely characterized effector mechanism.

Granuloma Formation

Immune cells form a granuloma to contain the infection, but sometimes the bacteria can break out, causing active TB.

Macrophage CL:0000235 T Cell CL:0000084

lipid metabolic process GO:0006629 cholesterol transport GO:0030301 inflammatory response GO:0006954

Lung UBERON:0002048

Experimental models

Autologous iPSC-derived alveolus-on-chip (iLoC) Mtb infection model ORGAN ON CHIP Large macrophage aggregates with a necrotic core arose stochastically and supported focal Mtb replication, an early necrotic-aggregate structure resembling the initiating step of granuloma formation.

Downstream

Tissue Damage Granuloma necrosis leads to cavitation and destruction of lung parenchyma.

Show evidence (6 references)

PMID:23626591 SUPPORT

"Granulomas are the hallmark of Mycobacterium tuberculosis (M.tb) infection and thus sit at the center of tuberculosis (TB) immunopathogenesis."

This review states granulomas are central to TB immunopathogenesis, supporting granuloma formation as a core mechanism.

PMID:14745511 SUPPORT

"The immune response to Mycobacterium tuberculosis (Mtb) infection is the formation of multicellular lesions, or granolomas, in the lung of the individual."

The reference describes the formation of granulomas in the lung as part of the immune response to Mtb infection, which aligns with the statement.

PMID:28577054 SUPPORT

"The typical composition is a center of macrophages/histiocytes with lymphocytes at the border."

The reference indicates the involvement of macrophages and T cells (lymphocytes) in granuloma formation, which supports the statement.

+ 3 more references

Neutrophil Activation and NETosis

Type I interferon-linked neutrophil programs drive NET formation contributing to tissue pathology, caseating necrosis, and vascular occlusion in progressive TB.

neutrophil CL:0000775

neutrophil degranulation GO:0043312 neutrophil extracellular trap formation GO:0140645

Lung UBERON:0002048

Downstream

Tissue Damage NETs contribute to immunopathology, tissue injury, and relapse risk in TB.

Tissue Damage

Active TB can cause cavitation and destruction of lung tissue.

Lung UBERON:0002048

Experimental models

Autologous iPSC-derived alveolus-on-chip (iLoC) Mtb infection model ORGAN ON CHIP Foci of aggregated cell death progressed to severe disruption of both the epithelial and endothelial layers, reproducing the barrier destruction that underlies tuberculous tissue damage.

Show evidence (4 references)

PMID:32482293 SUPPORT

"Cavitation is a dangerous consequence of pulmonary tuberculosis associated with poor outcomes, treatment relapse, higher transmission rates, and development of drug resistance."

The reference explicitly mentions cavitation as a severe consequence of pulmonary tuberculosis, which aligns with the statement.

PMID:27245780 SUPPORT

"Human TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation."

This reference provides evidence that TB lesions result in hypoxia and enzymatic activity that contributes to the destruction of lung tissue and cavitation.

PMID:16136463 SUPPORT

"Pulmonary cavitation with cough-generated aerosol is the principle means of spread, and lung remodeling (healed cavitation, fibrosis, and bronchiectasis) is a major cause of lung disability."

This reference discusses the relationship between TB, cavitation, and lung tissue remodeling, underscoring the statement that active TB causes cavitation and tissue damage.

+ 1 more reference

Drug Resistance Mechanisms

Development of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB through genetic mutations that confer resistance to first-line and second-line antitubercular drugs, driven by ineffective treatment regimens and irregular antibiotic exposure.

Downstream

Treatment Failure Drug-resistant TB strains render standard treatment regimens ineffective, leading to persistent infection and continued disease transmission.

Show evidence (1 reference)

PMID:42154079 SUPPORT

"There is also a discussion of the MTB lineage and the mutant types. The mechanisms of multidrug resistance and ineffective treatment regimens have driven advances in drug development and alternative therapeutics."

This comprehensive review explicitly addresses the mechanisms of multidrug resistance and the role of mutations in driving treatment failures and the need for novel therapeutics.

Immune Evasion

Mycobacterium tuberculosis employs mechanisms of bacterial pathogenesis to counteract the human defense system, contributing to drug resistance and chronic infection persistence.

Macrophage CL:0000235 T Cell CL:0000084

type I interferon signaling pathway GO:0060337 adaptive immune response GO:0002250

Experimental models

Autologous iPSC-derived alveolus-on-chip (iLoC) Mtb infection model ORGAN ON CHIP Neither macrophages nor epithelial cells were permissive to Mtb replication, in contrast to conventional two-dimensional cultures where Mtb replicates within 48 hours and to human disease where progressive intracellular replication is the norm. The chip therefore does not reproduce sustained evasion of intracellular killing, and replication appeared only in rare necrotic foci.

Show evidence (1 reference)

PMID:42154079 SUPPORT

"This comprehensive review introduces the mechanisms of bacterial pathogenesis against the human defence system and the development of drugs against MTB, with particular emphasis on the mechanisms of drug resistance and mutations that render them ineffective globally."

This review covers mechanisms by which MTB counteracts the human defense system, supporting pathogen-host immune interactions as a driver of chronic infection.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

Referential integrity issues (1):

Target 'Treatment Failure' (from 'Drug Resistance Mechanisms') not found in named elements

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Phenotypes

10

Cardiovascular 1

Lymphadenopathy OCCASIONAL HP:0002716

Swollen lymph nodes, especially in the neck

Show evidence (3 references)

PMID:30513392 SUPPORT

"TB can affect most organs in the head and neck region, such as the lymph nodes, larynx, middle ear, oral cavity and pharynx. In particular, as for cervical tuberculosis lymphadenopathy, a predominant involvement of the posterior triangle, supraclavicular, and internal jugular group of nodes..."

The literature supports that tuberculosis can cause lymphadenopathy, specifically in the neck region, but it does not provide a clear indication of frequency.

PMID:38317037 SUPPORT

"Other major causes of lymphadenopathy were metastatic tumor deposits, reactive lymphoid hyperplasia, and tuberculous lymphadenitis."

The literature indicates that tuberculous lymphadenitis is one of the major causes of lymphadenopathy, but it does not specify how frequently this occurs.

PMID:37743370 SUPPORT

"Close to half of patients with enlarged lymph nodes were positive for M. tuberculosis by the GeneXpert method in the study area."

The study shows a significant prevalence of TB lymphadenitis among patients with enlarged lymph nodes, but it does not provide a frequency classification such as 'occasional'.

Metabolism 1

Fever FREQUENT HP:0001945

Show evidence (3 references)

PMID:11120618 SUPPORT

"We describe three patients with recurrent fever thought to be due to tuberculosis, and review the 14 previously reported cases who fulfil the criteria of recurrent fever for at least 1 month's duration"

The literature indicates that fever is a frequent symptom associated with tuberculosis.

PMID:31641790 SUPPORT

"Tuberculosis is a bacterial infectious disease that is usually transmitted by inhalation of droplets containing the bacteria."

While this reference does affirm that tuberculosis causes systemic issues, it does not directly specify fever as a frequent phenotype.

PMID:18173876 SUPPORT

"SETTING: The diagnosis of tuberculosis (TB) may be rejected in the absence of symptoms such as fever, sweats or weight loss."

This reference notes the association of fever with tuberculosis but also highlights cases where fever may be absent, hence only partially supporting the statement.

Respiratory 3

Chronic Cough VERY_FREQUENT HP:0034315

Show evidence (3 references)

PMID:29196066 SUPPORT

"Cough is common in pulmonary TB and other chronic respiratory infections."

While cough is indeed a common symptom of pulmonary TB, the statement specifically categorizes chronic cough as very frequent, which is partially supported but not explicitly confirmed by the literature.

PMID:16131501 SUPPORT

"A persistent, non-remitting cough was reported in 15/16 (93.8%) children with tuberculosis."

This strongly supports the statement as it shows a high prevalence of a persistent chronic cough in children diagnosed with tuberculosis.

PMID:35710915 NO_EVIDENCE

"Initial microbiologic burdens and radiographic features also varied, including the presence of cavities and bilateral infiltration, which reflect TB-related severity."

This phenotype-clustering study describes microbiologic burden and radiographic features but the quoted text does not mention cough, so it does not directly support the chronic cough claim (tagged NO_EVIDENCE); frequency is supported by PMID:16131501.

Hemoptysis OCCASIONAL HP:0002105

Coughing up blood.

Show evidence (1 reference)

PMID:12816036 SUPPORT

"The most common causes of hemoptysis are tuberculosis, lung carcinoma, bronchiectasis but idiopathic forms are frequent."

The text states that tuberculosis is one of the most common causes of hemoptysis, supporting the statement.

Dyspnea OCCASIONAL HP:0002094

Shortness of breath

Show evidence (2 references)

PMID:15623010 NO_EVIDENCE

"Symptoms of pulmonary TB are a cough with or without sputum production lasting at least three weeks, chest pain, hemoptysis, fever, night sweats, weight loss, lack of appetite, chills and weakness."

The symptom list quoted here does not include dyspnea/shortness of breath, so this reference does not directly support dyspnea as a tuberculosis symptom (tagged NO_EVIDENCE).

PMID:29900887 SUPPORT

"Lung function impairment is known to occur after pulmonary TB irrespective of duration of treatment and outcome of disease."

This reference indicates that lung function issues, including dyspnea, can persist even after successful treatment of tuberculosis.

Constitutional 4

Night Sweats FREQUENT HP:0030166

Show evidence (3 references)

PMID:31599243 SUPPORT

"Cough, night sweat, fever, anorexia were significant presenting features."

The study documents night sweats as a significant symptom in TB patients.

PMID:12643362 SUPPORT

"Tuberculosis and lymphoma are diseases in which night sweats are a dominant symptom, but these are infrequently found to be the cause of night sweats in modern practice."

While night sweats are a notable symptom of TB, the reference suggests that in modern practice, they are less frequently the cause of night sweats compared to other conditions.

PMID:21813327 SUPPORT

"During therapy, fever, sweats, and dyspnea decreased most rapidly, with near resolution by the end of therapy."

The data supports the presence of night sweats as a frequent symptom in TB, with sweats reducing significantly during therapy.

Chest Pain FREQUENT HP:0100749

Often described as pleuritic chest pain

Show evidence (3 references)

PMID:17508531 SUPPORT

"Pleuritic chest pain is a common presenting symptom and has many causes, which range from life-threatening to benign, self-limited conditions."

The reference mentions pleuritic chest pain as a common symptom, but it does not specifically state that it is frequently associated with tuberculosis.

PMID:27499981 SUPPORT

"TPE usually presents as an acute illness with fever, cough and pleuritic chest pain."

This reference supports the statement as it explicitly mentions that tuberculous pleural effusion (a form of extrapulmonary tuberculosis) commonly presents with pleuritic chest pain.

PMID:30762202 NO_EVIDENCE

"Chest is the commonest site of involvement by tuberculosis (TB) in children; lungs being the most frequently affected region, followed by nodes, pleura and chest wall."

While this reference does not directly state chest pain, it supports the involvement of the chest in tuberculosis, which can be associated with pleuritic chest pain.

Fatigue OCCASIONAL HP:0012378

Show evidence (1 reference)

PMID:35189895 SUPPORT

"Patients with chronic fatigue syndrome and post-tuberculosis experience similar symptoms. Furthermore, chronic fatigue syndrome and tuberculosis share similar plasma immunosignatures."

The study indicates that tuberculosis can lead to symptoms similar to chronic fatigue syndrome, supporting the statement that fatigue can be a systemic symptom of tuberculosis.

Back Pain OCCASIONAL HP:0003418

May indicate spinal tuberculosis (Pott's disease)

Show evidence (4 references)

PMID:16882280 SUPPORT

"The findings of this study indicate that TB is a common cause of LBP that is liable to be overlooked in the differential diagnosis of LBP."

The study indicates that tuberculosis is a common cause of low back pain (LBP), supporting the statement that back pain may indicate spinal tuberculosis.

PMID:29358061 SUPPORT

"We present a case report of a military veteran presenting with neck pain and initially diagnosed with cervical disc disease. The patient's pain progressed to the point of developing paresthesias in his bilateral upper extremities. Eventually, cervical spine radiographs were obtained that..."

This case report supports the statement that back pain may indicate spinal tuberculosis, as it describes a patient whose neck pain was eventually diagnosed as spinal tuberculosis.

PMID:19845697 SUPPORT

"In TB spondylitis, the lumbar (22.7%) and thoracic (50%) vertebrae were the most commonly involved sites."

This study supports the statement by indicating that the lumbar and thoracic vertebrae are commonly involved in TB spondylitis, which can manifest as back pain.

+ 1 more reference

Growth 1

Weight Loss FREQUENT HP:0001824

Also known as consumption historically.

Show evidence (5 references)

PMID:36451280 SUPPORT

"Tuberculosis (TB) is well-known for causing wasting. Patients on treatment gain weight and weight loss is associated with unfavorable treatment outcomes."

This supports the statement that weight loss is a frequently observed systemic phenotype associated with tuberculosis.

PMID:38736083 SUPPORT

"Esophageal TB most commonly presents with dysphagia, odynophagia, retrosternal pain, and systemic symptoms like decreased appetite, loss of weight, and low-grade fever as associated or other presentations."

This reference supports the statement by indicating that weight loss is a common systemic symptom of esophageal tuberculosis.

PMID:23531875 SUPPORT Model Organism

"CBA/J mice may model these events, as sick mice share features with TB patients, including weight loss..."

Although the study is on mice, it draws parallels with human TB patients, reinforcing that weight loss is a frequently observed phenotype.

+ 2 more references

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Genetic Associations

8

TREM2 (Foamy macrophage formation and Mtb persistence)

Gene: TREM2 hgnc:17761

APOE (Lipid metabolism in TB-infected macrophages)

Gene: APOE hgnc:613

NPC2 (Lysosomal cholesterol handling)

Gene: NPC2 hgnc:14537

PLIN2 (Lipid droplet marker in foamy macrophages)

Gene: PLIN2 hgnc:248

LIPA (Lysosomal lipid catabolism)

Gene: LIPA hgnc:6617

TBK1 (Type I interferon signaling pathway)

Gene: TBK1 hgnc:11584

IRF3 (Interferon regulatory transcription factor)

Gene: IRF3 hgnc:6118

GBP4 (Type I interferon-inducible autophagy-dependent TB restriction)

Gene: GBP4 hgnc:20480

💊

Medical Actions

16

Isoniazid

Action: Pharmacotherapy NCIT:C15986

Agent: isoniazid CHEBI:6030

First-line antibiotic for TB treatment.

Show evidence (2 references)

PMID:33106268 SUPPORT

"Isoniazid (INH), one of the first-line drugs used for the treatment of tuberculosis, is a prodrug which is activated by the intracellular KatG enzyme of Mycobacterium tuberculosis."

The description of Isoniazid as a first-line antibiotic for TB treatment and its activation by the KatG enzyme is supported. This aligns with the provided mechanism of prodrug activation.

PMID:12164478 SUPPORT

"The drugs shown to inhibit mycolic acid biosynthesis are isoniazid, ethionamide, isoxyl, thiolactomycin, and triclosan."

The inhibition of mycolic acid biosynthesis by Isoniazid aligns with the described mechanism of action in the statement.

Rifampicin

Action: Pharmacotherapy NCIT:C15986

Agent: rifampicin CHEBI:28077

Bactericidal antibiotic used for TB treatment.

Show evidence (5 references)

PMID:11290327 SUPPORT

"Rifampicin (Rif) is one of the most potent and broad spectrum antibiotics against bacterial pathogens and is a key component of anti-tuberculosis therapy, stemming from its inhibition of the bacterial RNA polymerase (RNAP)."

This reference explains that Rifampicin is a key component of anti-tuberculosis therapy due to its inhibition of bacterial RNA polymerase.

PMID:27553018 SUPPORT

"For the treatment of TB, administration of multiple antibiotics such as isoniazid, rifampicin, pyrazinamide and ethambutol is required for a long period of time to kill bacteria."

This reference confirms that rifampicin is used for the treatment of TB.

PMID:34400805 SUPPORT

"Rifamycins exhibit bactericidal activity against many Gram-positive and Gram-negative bacteria by inhibiting RNA polymerase (RNAP)."

This reference supports the statement by confirming that Rifamycins, including rifampicin, exhibit bactericidal activity by inhibiting RNA polymerase.

+ 2 more references

Ethambutol

Action: Pharmacotherapy NCIT:C15986

Agent: ethambutol CHEBI:4877

Bacteriostatic antibiotic used for TB treatment.

Show evidence (3 references)

PMID:16209089 SUPPORT

"Ethambutol (EMB), the first line drug in the treatment of tuberculosis, is an inhibitor of the biosynthesis of the cell wall compound - arabinogalactan."

The literature states that ethambutol interferes with the biosynthesis of arabinogalactan, supporting the mechanism described in the statement.

PMID:9949810 SUPPORT

"Isoniazid is the most widely used antituberculosis drug."

The statement specifies ethambutol as a bacteriostatic antibiotic used for TB treatment, whereas this reference talks about isoniazid. It is partially relevant since ethambutol is also an antituberculosis drug, but this reference does not fully address ethambutol's function.

PMID:37289062 SUPPORT

"In combination with TB antibiotics, wollamide B1 synergistically enhances the activity of several antibiotics... and wollamide B1 did not compromise the antimycobacterial activity of the isoniazid/rifampicin/ethambutol combination."

This reference confirms that ethambutol is used in combination with other antitubercular drugs, aligning with the notes in the statement about preventing the emergence of drug resistance.

Drug-Resistant TB Regimen (BPaL/BPaLM)

Action: Pharmacotherapy NCIT:C15986

Agent: bedaquiline CHEBI:72292 linezolid CHEBI:63607 moxifloxacin CHEBI:63611

All-oral 6-month regimen of bedaquiline, pretomanid, and linezolid, with moxifloxacin added (BPaLM) for fluoroquinolone-susceptible disease, now recommended as first-line therapy for multidrug-resistant / rifampin-resistant TB in place of older 15-month-or-longer injectable-containing regimens.

Show evidence (2 references)

PMID:40693952 SUPPORT Other

"Drug-resistant TB recommendation updates include the use of novel regimens containing bedaquiline, pretomanid, and linezolid with or without moxifloxacin."

The 2025 ATS/CDC/ERS/IDSA guideline updates drug-resistant TB treatment to the all-oral bedaquiline/pretomanid/linezolid (with or without moxifloxacin) regimens.

PMID:40693952 SUPPORT Other

"We recommend BPaLM as the first line for MDR/RR-TB without fluoroquinolone resistance or intolerance."

The guideline gives a strong recommendation for BPaLM as first-line therapy for multidrug-resistant / rifampin-resistant TB lacking fluoroquinolone resistance.

Directly Observed Therapy (DOT)

Action: Pharmacotherapy NCIT:C15986

Health worker observes and records patients taking their medication to ensure adherence.

Show evidence (4 references)

PMID:17943789 SUPPORT

"Directly observed therapy (DOT), which involves people directly observing patients taking their antituberculous drugs."

The abstract clearly states that DOT involves someone directly observing patients taking their antituberculous drugs to ensure adherence.

PMID:29461901 SUPPORT

"The World Health Organization (WHO) propagates Directly Observed Therapy Short-course (DOTS) as an effective way to stop the spread of TB in communities with a high burden."

The abstract indicates that DOTS is endorsed by WHO as a method to ensure patients adhere to TB treatment.

PMID:28410705 SUPPORT

"A flexible, patient centered approach were a family member can act as the DOT provider with guidance from a trained health worker was evolved as the most acceptable and comfortable mode of treatment to majority of the TB patients"

The abstract reinforces the involvement of a health worker in observing DOT, even if it's flexible to involve family members.

+ 1 more reference

Latent TB Treatment

Action: Pharmacotherapy NCIT:C15986

Isoniazid or rifapentine used to prevent latent TB from becoming active.

Show evidence (3 references)

PMID:29910114 SUPPORT

"The 3-month isoniazid-rifapentine regimen is as safe and effective as other recommended latent tuberculosis infection regimens and achieves significantly higher treatment completion rates."

This source supports the statement mentioning that a regimen of isoniazid and rifapentine is used for latent TB infection.

PMID:19496388 SUPPORT

"The treatment of choice for LTBI is isoniazid for nine months."

This source supports the use of isoniazid for the prevention of latent tuberculosis infection (LTBI).

PMID:32551948 SUPPORT

"The World Health Organization recommends the use of isoniazid (INH) alone or in combination with rifapentine to treat latent tuberculosis infections."

This supports the statement by specifying that WHO recommends isoniazid and rifapentine for the treatment of latent tuberculosis infections.

Host-Directed Therapy

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Adjunctive strategies to enhance autophagy, modulate inflammasome activity, or reprogram macrophage lipid metabolism alongside standard antibiotics.

SQ109

Action: Pharmacotherapy NCIT:C15986

Agent: SQ109 CHEBI:188155

Investigational ethylenediamine compound being explored for activity against drug-resistant M. tuberculosis, derived from ethambutol pharmacophore development.

Show evidence (1 reference)

PMID:42154079 SUPPORT

"New molecules that can potentially disarm MTB have been explored, including SQ109, GuaB2, Q203, Largazole, and Auranofin."

Novel compound identified as having potential to address MTB drug resistance.

GuaB2

Action: Pharmacotherapy NCIT:C15986

Inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH, encoded by guaB2) in M. tuberculosis, a validated drug target essential for guanine nucleotide biosynthesis.

Show evidence (1 reference)

PMID:42154079 SUPPORT

"New molecules that can potentially disarm MTB have been explored, including SQ109, GuaB2, Q203, Largazole, and Auranofin."

Novel compound identified as having potential to address MTB drug resistance.

Q203

Action: Pharmacotherapy NCIT:C15986

Emerging TB drug candidate (telacebec) being explored for activity against multidrug-resistant and extensively drug-resistant TB.

Show evidence (1 reference)

PMID:42154079 SUPPORT

"New molecules that can potentially disarm MTB have been explored, including SQ109, GuaB2, Q203, Largazole, and Auranofin."

Novel compound identified as having potential to address MTB drug resistance.

Largazole

Action: Pharmacotherapy NCIT:C15986

Agent: largazole CHEBI:212400

Cyclodepsipeptide natural product (histone deacetylase inhibitor) with potential antimycobacterial activity being explored as a novel TB therapeutic.

Show evidence (1 reference)

PMID:42154079 SUPPORT

"New molecules that can potentially disarm MTB have been explored, including SQ109, GuaB2, Q203, Largazole, and Auranofin."

Novel compound identified as having potential to address MTB drug resistance.

Auranofin

Action: Pharmacotherapy NCIT:C15986

Agent: auranofin CHEBI:2922

Gold-containing compound (originally approved for rheumatoid arthritis) being explored for antimycobacterial activity in repurposing programs for TB treatment, particularly in drug-resistant cases.

Show evidence (1 reference)

PMID:42154079 SUPPORT

"New molecules that can potentially disarm MTB have been explored, including SQ109, GuaB2, Q203, Largazole, and Auranofin."

Novel compound identified as having potential to address MTB drug resistance.

Natural Compound Therapy

Action: Pharmacotherapy NCIT:C15986

Exploration of natural compounds as adjunctive or alternative approaches for TB treatment.

Show evidence (1 reference)

PMID:42154079 SUPPORT

"natural compounds, bacteriophage therapy, antimicrobial peptides, and probiotics are also explored to help address the global threat posed by MTB."

Emerging therapeutic modalities beyond conventional antibiotics being evaluated for TB treatment.

Bacteriophage Therapy

Action: Pharmacotherapy NCIT:C15986

Use of bacteriophages (viruses that infect bacteria) as alternative antimicrobial agents against M. tuberculosis.

Show evidence (1 reference)

PMID:42154079 SUPPORT

"natural compounds, bacteriophage therapy, antimicrobial peptides, and probiotics are also explored to help address the global threat posed by MTB."

Emerging therapeutic modality being investigated to combat MTB and address antibiotic resistance.

Antimicrobial Peptide Therapy

Action: Pharmacotherapy NCIT:C15986

Use of synthetic or naturally-derived peptides with antimicrobial properties against M. tuberculosis.

Show evidence (1 reference)

PMID:42154079 SUPPORT

"natural compounds, bacteriophage therapy, antimicrobial peptides, and probiotics are also explored to help address the global threat posed by MTB."

Emerging therapeutic modality being investigated to combat MTB and address antibiotic resistance.

Probiotic Therapy

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Use of beneficial microorganisms to enhance immune function and support conventional TB treatment.

Show evidence (1 reference)

PMID:42154079 SUPPORT

"natural compounds, bacteriophage therapy, antimicrobial peptides, and probiotics are also explored to help address the global threat posed by MTB."

Emerging therapeutic modality being investigated to combat MTB and address antibiotic resistance.

🔬

Biochemical Markers

2

Tuberculin Skin Test (TST) (Positive)

Show evidence (1 reference)

PMID:25440529 SUPPORT

"Worldwide, tuberculin skin tests (TSTs) commonly give false positive results for those who had been given the Bacillus-Calmette-Guerin vaccine such as is routinely administered in Turkey."

While mentioning the possibility of false positives due to BCG vaccination, the reference acknowledges that positive TST results primarily indicate TB infection.

Interferon-Gamma Release Assay (IGRA) (Positive)

Show evidence (5 references)

PMID:28220979 SUPPORT

"TB-IGRA results were in positive proportion to the lymphocytes, CD4(+) T cells and CD4(+) CD28(+) T cells, whereas negative to the Treg cells."

This study discusses the positive TB-IGRA test results in patients infected with tuberculosis, supporting the statement that a positive IGRA indicates TB infection.

PMID:26018533 SUPPORT

"Recently, two new diagnostic tests have been introduced; these two new tests can detect TB infection in patients by challenging peripheral blood cells with specific TB proteins."

The abstract confirms that the Interferon-Gamma Release Assay (IGRA) is a blood test used to detect TB infection.

PMID:33276277 SUPPORT Model Organism

"Accurate and early detection of M. bovis infection in buffaloes is important for controlling transmission. Assays that detect cell-mediated immune responses to M. bovis in buffaloes have been developed although these often display suboptimal sensitivity or specificity."

This study discusses IGRA as a diagnostic tool for detecting TB infections, supporting the claim.

+ 2 more references

🔬

Diagnosis

3

Sputum Microscopy (Positive)

Microscopic examination of sputum samples stained with Ziehl-Neelsen or auramine to identify acid-fast bacilli.

Detection of acid-fast bacilli.

Show evidence (6 references)

PMID:30054578 SUPPORT

"We developed and evaluated an operator-independent microscopic examination of sputum smears for the automated detection and enumeration of acid-fast bacilli using a ZEISS Axio Scan.Z1 microscope."

The study supports that sputum microscopy can detect acid-fast bacilli. It emphasizes an automated method but still aligns with the use of sputum microscopy for diagnosis.

PMID:15535337 SUPPORT

"Sputum direct smear was positive for acid-fast bacilli in only 22.8% of patients and 11.2% were diagnosed base on positive sputum culture"

This study confirms that sputum microscopy can detect acid-fast bacilli, but it also highlights instances where sputum may be negative even in TB patients.

PMID:27847013 SUPPORT

"Of the 100 ZN positive specimens, 74 were FDA positive of which 70 were reported positive by both the readers."

Sputum microscopy positivity for acid-fast bacilli is mentioned but the study's focus is on the FDA staining method.

+ 3 more references

Chest X-Ray

Radiographic imaging to identify pulmonary infiltrates, cavitations, and hilar lymphadenopathy characteristic of TB.

Shows cavitary lesions and other signs of active pulmonary TB.

Show evidence (4 references)

PMID:24429302 SUPPORT

"The chest radiograph (CXR) is a key initial tool in the diagnosis of many lung conditions, including pulmonary tuberculosis (TB). With proper use of anti-tuberculosis drugs, TB can be treated effectively and many CXR changes are limited."

This reference establishes that chest radiographs (CXRs) are key tools in diagnosing pulmonary tuberculosis, supporting the statement that chest X-ray is used in the diagnosis of TB.

PMID:37977833 SUPPORT

"Follow-up CT showed CS progressing to a cavitatory shadow and GS intensification. The detection of Mycobacterium tuberculosis (M. tuberculosis) in a subsequent sputum analysis prompted treatment with antitubercular drugs, leading to symptom relief."

This reference supports the statement regarding the use of chest X-rays in diagnosing TB as it discusses how chest CT (an advanced form of X-ray) shows cavitary lesions, which are indicative of active pulmonary TB.

PMID:8553964 SUPPORT

"Radiographic findings consistent with active pulmonary TB were present in all patients."

This reference reinforces the use of radiographic imaging (including chest X-rays) in identifying active pulmonary TB.

+ 1 more reference

Sputum Culture (Positive)

Growth of Mycobacterium tuberculosis on solid or liquid media, the gold standard for diagnosis.

Confirms TB diagnosis.

Show evidence (6 references)

PMID:10970761 SUPPORT

"However, the sensitivity of sputum smear for acid-fast bacteria is only approximately 50% and sputum culture has a relatively long turnaround time."

While sputum culture is considered important for TB diagnosis, it has limitations such as long turnaround time which may affect its utility in confirming TB diagnosis promptly.

PMID:31666021 SUPPORT

"Pulmonary tuberculosis (TB) with detectable Mycobacterium tuberculosis in the sputum is a major source of transmission."

Although this article acknowledges the importance of sputum smear for transmission evaluation, it also highlights that viable bacteria may still be present in some 'cured' patients, indicating a limitation in using sputum alone for confirming cure.

PMID:32755530 SUPPORT

"Poor-quality cough specimens (n=61) from presumptive tuberculosis cases were cultured and GeneXpert MTB/RIF (Xpert) successfully performed on samples transferred by flocked swab into PrimeStore molecular transport medium (PS-MTM). Mycobacterium tuberculosis was grown in culture from 13 (21.3 %)."

Supports the idea that sputum culture can confirm TB diagnosis, even from poor-quality specimens.

+ 3 more references

📈

Progression

2

Latent

Duration: Variable

Non-contagious stage where the bacteria are present in the body but inactive.

Show evidence (2 references)

PMID:30021818 SUPPORT

"Human TB infection, from latent infection to active disease, exists within a continuous spectrum of metabolic bacterial activity and antagonistic immunological responses."

This reference supports the concept of variable progression within the latent phase but does not explicitly refer to the duration being variable or confirm the non-contagious stage where bacteria are inactive.

PMID:23460007 SUPPORT

"Latent tuberculosis infection (LTBI) refers to a circumstance in which viable Mycobacterium tuberculosis (MTB) bacilli are present in an individual but symptoms and signs of active disease are lacking, and the bacilli are relatively inactive metabolically."

The reference directly supports the statement that during the latent phase, tuberculosis is in a non-contagious stage where the bacteria are present but inactive.

Active

Duration: Variable

Contagious stage where symptoms appear and the bacteria can be spread to others.

Show evidence (3 references)

PMID:30021818 SUPPORT

"Recent research has clearly demonstrated that human TB infection, from latent infection to active disease, exists within a continuous spectrum of metabolic bacterial activity and antagonistic immunological responses."

This indicates the variable duration of progression from latent to active TB, supporting the statement.

PMID:37094782 SUPPORT

"In this cohort, children and adolescents diagnosed with TB experienced symptoms for a median of 85 days (interquartile range: 30, 231 days) prior to treatment initiation."

The variable duration of symptom onset supports the statement.

PMID:35704248 SUPPORT

"The system considers demographic structure coupling with the continuous development of disease stage, which is crucial for studying how aging affects tuberculosis dynamics and disease progression."

This implies that TB progression has a variable duration depending on individual factors like age.

📊

Prevalence

2

Global

Point Prevalence 23670.0 per 100,000 >1 in 1,000

Latent TB infection (LTBI) prevalence; distinct from active TB disease incidence. Globally decreased from 30.66% (1990) to 23.67% (2019). Approximately 1.7 billion people carry latent Mtb infection.

Show evidence (2 references)

PMID:35577247 SUPPORT

"Globally, the prevalence rate of LTBI decreased from 30.66% in 1990 to 23.67% in 2019, with an AAPC of -0.9%."

Direct quantitative estimate of global latent TB infection point prevalence (~23.67% as of 2019).

PMID:30454918 SUPPORT

"An estimated 1.7 billion (23%) of the world’s population is infected with Mycobacterium tuberculosis leading to more than 10 million new tuberculosis (TB) cases each year."

Corroborates ~23% global LTBI prevalence (1.7 billion infected); also provides active TB incidence estimate.

Global

Annual Incidence 130.0 per 100,000 >1 in 1,000 per year

Active TB disease incidence; substantially lower than LTBI prevalence. Approximately 10 million new active TB cases per year (ca. 2019). Sex ratio approximately 2:1 male-to-female.

Show evidence (1 reference)

PMID:30454918 SUPPORT

"An estimated 1.7 billion (23%) of the world’s population is infected with Mycobacterium tuberculosis leading to more than 10 million new tuberculosis (TB) cases each year."

Active TB incidence of >10 million new cases per year (ca. 2019) corresponds to approximately 130 per 100,000 globally.

🦠

Infectious Agent

1

Mycobacterium tuberculosis

A bacterium that primarily affects the lungs but can affect other organs.

Mycobacterium tuberculosis NCBITaxon:1773

Show evidence (3 references)

PMID:27784885 SUPPORT

"Tuberculosis (TB) is an airborne infectious disease caused by organisms of the Mycobacterium tuberculosis complex. Although primarily a pulmonary pathogen, M. tuberculosis can cause disease in almost any part of the body."

The statement correctly identifies Mycobacterium tuberculosis as a bacterium that primarily affects the lungs but can affect other organs.

PMID:37057936 SUPPORT

"Mycobacterium tuberculosis belongs to the group of mycobacteria, most of which can cause a delayed hypersensitivity reaction in the body and is a bacterium that causes tuberculosis."

This reference confirms that Mycobacterium tuberculosis is a bacterium that causes TB and can affect the lungs.

PMID:33306806 SUPPORT

"Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB). It spreads from one person to the another through the air while coughing, spitting, speaking or sneezing. TB most commonly affects lungs but it can affect any organ system."

This reference supports the claim that tuberculosis, caused by Mycobacterium tuberculosis, primarily affects the lungs but can also affect other organ systems.

↔️

Transmission

1

Airborne Transmission

Spread through the air when individuals with active TB cough, sneeze, or speak.

Show evidence (5 references)

PMID:6338584 SUPPORT

"Subsequent evidence has indicated that direct contact is unimportant, although close proximity facilitates airborne transmission."

The literature confirms airborne transmission of tuberculosis and mentions that direct contact is unimportant in its spread.

PMID:20529335 SUPPORT

"Tuberculosis is a highly infectious disease that is spread from person to person by infected aerosols emitted by patients with respiratory forms of the disease."

This excerpt explicitly states that TB is spread by aerosols generated by respiratory activities.

PMID:26198113 SUPPORT

"Tuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis (MTB) that usually affects the lungs leading to severe coughing, fever, and chest pains."

This statement confirms that TB is an airborne disease.

+ 2 more references

📊

Related Datasets

9

Spatial transcriptomic profiling of alveoli and granuloma regions in patients with active pulmonary tuberculosis geo:GSE301876

Spatial transcriptomic profiling was performed using the GeoMx DSP Whole Transcriptome Atlas to measure expression of over 18,000 genes in alveoli and granuloma core and mantle regions from patients with active pulmonary tuberculosis. Differential gene expression revealed region-specific transcriptional profiles, including signatures related to antimicrobial response and lipid metabolism.

human SPATIAL TRANSCRIPTOMICS n=180

PMID:40791339

Identified by GEO DataSets index search for Tuberculosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Diabetes mellitus is associated with a shared hyper-inflammatory immune response in melioidosis and tuberculosis patients: an observational case-control study geo:GSE296546

Melioidosis is a serious infection caused by the bacterium Burkholderia pseudomallei (Bp) with a case fatality rate of up to 40% in Northeast Thailand. Diabetes increases the risk of developing melioidosis by 12-fold. A similar, but less marked, relationship with diabetes is seen in tuberculosis (TB) patients, with a 3-fold increased risk of developing TB in people with diabetes. However, the mechanisms underlying increased susceptibility are not fully understood. Whole blood samples of 81 acute melioidosis patients from Northeast Thailand and 151 TB patients from South Africa, Indonesia, Romania and Peru alongside uninfected control cohorts were studied by whole blood RNA sequencing.

human BULK RNA SEQ n=110

PMID:42318305

Identified by GEO DataSets index search for Tuberculosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

A unique Mitochondrial Quality Control (MQC) mechanism reverses the phagosome maturation arrest caused by Mycobacterium tuberculosis geo:GSE216985

Phagosome maturation arrest (PMA) imposed by Mycobacterium tuberculosis (Mtb) is among the classic tools that helps Mtb evade macrophage anti-bacterial response. Here we report a unique crosstalk between mitochondrial quality control (MQC) pathways and the phagosome maturation pathway, which unblocks the PMA and results in the efficient killing of Mtb. Depletion of p62/SQSTM1, a major autophagy adaptor, in human macrophages enhances Mtb killing. However, depletion of p62/SQSTM1 does not impact mitochondrial quality, despite an apparent block in mitophagy flux. Interestingly, in p62KD cells, MQC is ensured via TOM20+-mitochondria-derived vesicles (MDVs).

human BULK RNA SEQ n=36

Identified by GEO DataSets index search for Tuberculosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

WTCCC case-control study for Tuberculosis ega:EGAS00000000027

WTCCC genome-wide case-control association study for Tuberculosis (TB) using the African samples as controls.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Tuberculosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Russian GWAS of tuberculosis ega:EGAS00001001089

Genome-wide association study of cases of tuberculosis from St. Petersburg and Samara, in Russia, compared to healthy controls from the same two cities. Genotyped using the Affy6 platform.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Tuberculosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

GWAS of tuberculosis in Russia ega:EGAS00001001090

Genome-wide association study of cases of tuberculosis from St Petersburg and Samara, in Russia, compared to healthy controls from the same two cities. Genotype data from Affy6 array.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Tuberculosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Mycobacterium tuberculosis normoxia hypoxia reactivation with ActivX-desthiobiotin FP probe massive:MSV000080238

Lysates of Mycobacterium tuberculosis (H37Rv auxotroph mc(2)6020) grown under various conditions (normoxia, hypoxia, reactivation from hypoxia) probed the serine hydrolase probe with ActivX-desthiobiotin FP.

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Tuberculosis"). Retrieved 2026-08-02.

The Mycobacterium tuberculosis O-phosphorylation landscape massive:MSV000088254

LC-MS/MS tryptic peptide data comprising both label free (phosphoproteome) and TMT10 (global and phosphoproteome) analysis of mycobacterium tuberculosis mutants (WT, GoF, and LoF) grown at stationary phase. Data was searched with MS-GF+ (TMT) and MaxQuant (label free).

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Tuberculosis"). Retrieved 2026-08-02.

GeLC-MS/MS of H37Rv and two clinical isolates of Mycobacterium tuberculosis massive:MSV000081205

Clinical isolates were made available from an extensive longitudinal collection of M. tuberculosis isolates circulating in the Western Cape of South Africa. Clinical isolates SAWC3651 and SAWC3517, belonging to the LAM (lineage 4.3) genotype and IS6110 family 14 and 9, respectively, and M. tuberculosis H37Rv were selected for analysis. Proteins were fractionated by SDS-PAGE, using a 4-12% gradient, 1.0 mm NuPage gel (Invitrogen, Carlsbad, CA, USA). Each gel lane was divided into 10 fractions and each fraction was prepared for analysis by mass spectrometry.

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Tuberculosis"). Retrieved 2026-08-02.

🔬

Clinical Trials

1

NCT03568383 PHASE_III

Open-label randomized prophylaxis study comparing delamanid versus isoniazid for preventing active tuberculosis among high-risk household contacts of adults with multidrug-resistant TB over 96 weeks of follow-up.

Show evidence (1 reference)

clinicaltrials:NCT03568383 SUPPORT

"The purpose of this study is to compare the efficacy and safety of 26 weeks of delamanid (DLM) versus 26 weeks of isoniazid (INH) for preventing confirmed or probable active tuberculosis (TB) during 96 weeks of follow-up among high-risk household contacts (HHCs) of adults with..."

This trial evaluates delamanid as preventive therapy for household contacts of MDR-TB patients, directly relevant to tuberculosis control strategies.

🧫

Experimental Models

1

Autologous iPSC-derived alveolus-on-chip (iLoC) Mtb infection model ORGAN_ON_CHIP namo:OrganOnChip

A single-donor human iPSC-derived lung-on-chip containing alveolar type 1 and type 2 epithelial cells, vascular endothelial cells, and iPSC-derived macrophages, under air-liquid interface with three-dimensional cyclic stretch. Because every cell type derives from one donor, the model is autologous and genetically tractable: an ATG14 knockout confined to the macrophage compartment can be combined with wild-type epithelium and endothelium to isolate a cell-type-specific autophagy requirement, which is not achievable in a patient or in a whole-animal knockout.

Organism

human NCBITaxon:9606

Tissue

alveolus of lung UBERON:0002299

Cell source

Single-donor human induced pluripotent stem cells (autologous across all compartments)

Culture

Microfluidic alveolus-on-chip with air-liquid interface and cyclic mechanical stretch

Publication

PMID:41477823

Pathograph links

Phagocytosis recapitulates fidelity: moderate Alveolar macrophages and epithelial cells take up Mtb, reproducing the initial uptake step in a human alveolar microenvironment.

Limitations: The macrophage compartment is iPSC-derived rather than tissue-resident alveolar macrophage, and the chip carries no recruited neutrophils or lymphocytes, so uptake occurs without the wider cellular context of a human alveolus.

Readouts

Intracellular Mtb in macrophages and alveolar epithelium

Direction: INCREASED

Interpretation: Confirms uptake of bacilli by both compartments after infection.

Show evidence (1 reference)

PMID:41477823 SUPPORT In Vitro

"Infection of the iLoC with the human pathogen Mycobacterium tuberculosis (Mtb) showed that both macrophages and epithelial cells were infected but not permissive to bacterial replication."

Documents uptake into both cell compartments, the readout for this node.

Show evidence (1 reference)

PMID:41477823 SUPPORT In Vitro

"Together, we report an autologous, genetically tractable human alveolar model to study lung diseases and therapies."

Supports treating the chip as an informative human alveolar model for early infection events.

GBP4-Mediated Autophagy-Dependent TB Restriction perturbs fidelity: moderate A macrophage-restricted ATG14 knockout tests the autophagy requirement directly. The result refines the usual framing: ATG14 loss raised macrophage necrosis without permitting bacterial replication, separating autophagy's role in host-cell survival from its role in bacterial restriction.

Limitations: ATG14 is not GBP4, and the chip result speaks to the autophagy machinery this node invokes rather than to GBP4 specifically. The perturbation is also a complete knockout rather than the partial, regulated variation seen in human infection.

Readouts

Macrophage necrosis in ATG14-knockout versus wild-type macrophages

Direction: INCREASED

Interpretation: Autophagy deficiency increases infected-macrophage death without increasing bacterial burden, indicating the pathway protects the host cell rather than only restricting the bacterium here.

Show evidence (1 reference)

PMID:41477823 SUPPORT In Vitro

"A genetically engineered autophagy-deficient iLoC revealed that after Mtb infection, macrophage necrosis was higher upon ATG14 deficiency without bacterial replication."

The direct readout of the autophagy perturbation in this model.

Show evidence (1 reference)

PMID:41477823 SUPPORT In Vitro

"Using a genetically engineered ATG14KO hybrid GE-iLoC, we found that ATG14-deficient macrophages are more susceptible to cell death under homeostatic and Mtb-infected conditions."

Supports the chip as a system for interrogating autophagy dependence in this node.

Granuloma Formation partially recapitulates fidelity: low Large macrophage aggregates with a necrotic core arose stochastically and supported focal Mtb replication, an early necrotic-aggregate structure resembling the initiating step of granuloma formation.

Limitations: These aggregates are not granulomas. They lack lymphocytic cuffing, epithelioid and multinucleate giant-cell differentiation, and fibrotic encapsulation, form only stochastically, and arise over days rather than the weeks of granuloma maturation in vivo. The chip has no adaptive immune compartment, so the T-cell-dependent stages cannot occur at all.

Readouts

Macrophage aggregates with necrotic core supporting focal Mtb replication

Direction: INCREASED

Interpretation: A necrotic-core aggregate is the earliest structural correlate of granuloma initiation available in this system.

Show evidence (1 reference)

PMID:41477823 SUPPORT In Vitro

"Stochastically, large macrophage clusters containing necrotic macrophages supporting Mtb replication were observed."

Reports the necrotic macrophage aggregate; PARTIAL because a stochastic aggregate is only the initiating step of the granuloma this node describes.

Show evidence (1 reference)

PMID:41477823 SUPPORT In Vitro

"Stochastically, large macrophage clusters containing necrotic macrophages supporting Mtb replication were observed."

Supports limited, early-stage relevance of the chip to granuloma formation.

Tissue Damage recapitulates fidelity: moderate Foci of aggregated cell death progressed to severe disruption of both the epithelial and endothelial layers, reproducing the barrier destruction that underlies tuberculous tissue damage.

Limitations: Damage is confined to the two cellular layers on the chip; there is no matrix remodelling, cavitation, or vascular thrombosis, which are central to tissue damage in human pulmonary tuberculosis.

Readouts

Epithelial and endothelial barrier integrity

Direction: DECREASED

Interpretation: Barrier destruction at foci of cell death is the tissue-damage readout in this model.

Show evidence (1 reference)

PMID:41477823 SUPPORT In Vitro

"However, we observed areas of cell death aggregation and Mtb replication that progressed to a severe disruption of both the epithelial and endothelial barrier."

Directly reports the barrier destruction this readout measures.

Show evidence (1 reference)

PMID:41477823 SUPPORT In Vitro

"However, we observed areas of cell death aggregation and Mtb replication that progressed to a severe disruption of both the epithelial and endothelial barrier."

Supports the chip as informative for tuberculous alveolar tissue damage.

Immune Evasion fails to recapitulate fidelity: low Neither macrophages nor epithelial cells were permissive to Mtb replication, in contrast to conventional two-dimensional cultures where Mtb replicates within 48 hours and to human disease where progressive intracellular replication is the norm. The chip therefore does not reproduce sustained evasion of intracellular killing, and replication appeared only in rare necrotic foci.

Limitations: Non-permissiveness may reflect the immaturity of iPSC-derived macrophages, the absence of the immunosuppressive signals of an established lesion, or the short observation window, rather than a genuine property of the human alveolus. Until that is resolved, the model should not be used to score evasion phenotypes or to screen compounds whose readout is restriction of intracellular replication.

Readouts

Intracellular Mtb replication over 48 hours

Direction: UNCHANGED

Interpretation: Absence of replication where 2D culture and human disease both show it is a negative result that bounds the model's use.

Show evidence (1 reference)

PMID:41477823 REFUTE In Vitro

"In the iLoC, macrophages and epithelial cells are not permissive for Mtb replication as compared to 2D in vitro cultures."

Explicit statement that the model does not support the intracellular replication that immune evasion in human tuberculosis entails.

Show evidence (1 reference)

PMID:41477823 REFUTE In Vitro

"In the iLoC, macrophages and epithelial cells are not permissive for Mtb replication as compared to 2D in vitro cultures."

Substantiates the negative claim that this model fails to recapitulate sustained intracellular persistence.

{ }

Source YAML

click to show

name: Tuberculosis
creation_date: '2025-12-04T16:57:31Z'
description: Tuberculosis is a contagious bacterial infection caused by Mycobacterium tuberculosis that primarily affects the lungs but can involve any organ. It spreads through airborne transmission and can exist in latent or active forms, with the active form causing characteristic symptoms including chronic cough, fever, night sweats, and weight loss.
category: Infectious Disease
parents:
- Bacterial Infection
infectious_agent:
- name: Mycobacterium tuberculosis
  infectious_agent_term:
    preferred_term: Mycobacterium tuberculosis
    term:
      id: NCBITaxon:1773
      label: Mycobacterium tuberculosis
  description: A bacterium that primarily affects the lungs but can affect other organs.
  evidence:
  - reference: PMID:27784885
    reference_title: "Tuberculosis."
    supports: SUPPORT
    snippet: Tuberculosis (TB) is an airborne infectious disease caused by organisms of the Mycobacterium tuberculosis complex. Although primarily a pulmonary pathogen, M. tuberculosis can cause disease in almost any part of the body.
    explanation: The statement correctly identifies Mycobacterium tuberculosis as a bacterium that primarily affects the lungs but can affect other organs.
  - reference: PMID:37057936
    reference_title: "Mycobacterium Tuberculosis Infection in AECOPD Combined with Pulmonary Embolism: a Case Report."
    supports: SUPPORT
    snippet: Mycobacterium tuberculosis belongs to the group of mycobacteria, most of which can cause a delayed hypersensitivity reaction in the body and is a bacterium that causes tuberculosis.
    explanation: This reference confirms that Mycobacterium tuberculosis is a bacterium that causes TB and can affect the lungs.
  - reference: PMID:33306806
    reference_title: "Poncet's Disease: A Case Report."
    supports: SUPPORT
    snippet: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB). It spreads from one person to the another through the air while coughing, spitting, speaking or sneezing. TB most commonly affects lungs but it can affect any organ system.
    explanation: This reference supports the claim that tuberculosis, caused by Mycobacterium tuberculosis, primarily affects the lungs but can also affect other organ systems.
transmission:
- name: Airborne Transmission
  description: Spread through the air when individuals with active TB cough, sneeze, or speak.
  evidence:
  - reference: PMID:6338584
    reference_title: "The contagiosity of tuberculosis."
    supports: SUPPORT
    snippet: Subsequent evidence has indicated that direct contact is unimportant, although close proximity facilitates airborne transmission.
    explanation: The literature confirms airborne transmission of tuberculosis and mentions that direct contact is unimportant in its spread.
  - reference: PMID:20529335
    reference_title: "Field test of a novel detection device for Mycobacterium tuberculosis antigen in cough."
    supports: SUPPORT
    snippet: Tuberculosis is a highly infectious disease that is spread from person to person by infected aerosols emitted by patients with respiratory forms of the disease.
    explanation: This excerpt explicitly states that TB is spread by aerosols generated by respiratory activities.
  - reference: PMID:26198113
    reference_title: "Tuberculosis: a disease without boundaries."
    supports: SUPPORT
    snippet: Tuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis (MTB) that usually affects the lungs leading to severe coughing, fever, and chest pains.
    explanation: This statement confirms that TB is an airborne disease.
  - reference: PMID:34639431
    reference_title: "Occupational Risk of Airborne Mycobacterium tuberculosis Exposure: A Situational Analysis in a Three-Tier Public Healthcare System in South Africa."
    supports: SUPPORT
    snippet: Airborne MTB was detected in 2.2% of samples (13/572), and 97.8% were negative.
    explanation: The study provides empirical evidence of the presence of Mycobacterium tuberculosis in the air, supporting airborne transmission.
  - reference: PMID:30307321
    reference_title: "Potential of dry powder inhalers for tuberculosis therapy: facts, fidelity and future."
    supports: SUPPORT
    snippet: Tuberculosis (TB) is a contagious and airborne infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb).
    explanation: This reference also reaffirms that TB is an airborne infectious disease.
prevalence:
- population: Global
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 23670.0
  notes: Latent TB infection (LTBI) prevalence; distinct from active TB disease incidence. Globally decreased from 30.66% (1990) to 23.67% (2019). Approximately 1.7 billion people carry latent Mtb infection.
  evidence:
  - reference: PMID:35577247
    reference_title: "Prevalence trends of latent tuberculosis infection at the global, regional, and country levels from 1990-2019."
    supports: SUPPORT
    snippet: Globally, the prevalence rate of LTBI decreased from 30.66% in 1990 to 23.67% in 2019, with an AAPC of -0.9%.
    explanation: Direct quantitative estimate of global latent TB infection point prevalence (~23.67% as of 2019).
  - reference: PMID:30454918
    reference_title: "The Global Fight Against Tuberculosis."
    supports: SUPPORT
    snippet: An estimated 1.7 billion (23%) of the world’s population is infected with Mycobacterium tuberculosis leading to more than 10 million new tuberculosis (TB) cases each year.
    explanation: Corroborates ~23% global LTBI prevalence (1.7 billion infected); also provides active TB incidence estimate.
- population: Global
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 130.0
  notes: Active TB disease incidence; substantially lower than LTBI prevalence. Approximately 10 million new active TB cases per year (ca. 2019). Sex ratio approximately 2:1 male-to-female.
  evidence:
  - reference: PMID:30454918
    reference_title: "The Global Fight Against Tuberculosis."
    supports: SUPPORT
    snippet: An estimated 1.7 billion (23%) of the world’s population is infected with Mycobacterium tuberculosis leading to more than 10 million new tuberculosis (TB) cases each year.
    explanation: Active TB incidence of >10 million new cases per year (ca. 2019) corresponds to approximately 130 per 100,000 globally.
progression:
- phase: Latent
  duration: Variable
  notes: Non-contagious stage where the bacteria are present in the body but inactive.
  evidence:
  - reference: PMID:30021818
    reference_title: "Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection."
    supports: SUPPORT
    snippet: Human TB infection, from latent infection to active disease, exists within a continuous spectrum of metabolic bacterial activity and antagonistic immunological responses.
    explanation: This reference supports the concept of variable progression within the latent phase but does not explicitly refer to the duration being variable or confirm the non-contagious stage where bacteria are inactive.
  - reference: PMID:23460007
    reference_title: "Treatment of latent tuberculosis infection."
    supports: SUPPORT
    snippet: Latent tuberculosis infection (LTBI) refers to a circumstance in which viable Mycobacterium tuberculosis (MTB) bacilli are present in an individual but symptoms and signs of active disease are lacking, and the bacilli are relatively inactive metabolically.
    explanation: The reference directly supports the statement that during the latent phase, tuberculosis is in a non-contagious stage where the bacteria are present but inactive.
- phase: Active
  duration: Variable
  notes: Contagious stage where symptoms appear and the bacteria can be spread to others.
  evidence:
  - reference: PMID:30021818
    reference_title: "Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection."
    supports: SUPPORT
    snippet: Recent research has clearly demonstrated that human TB infection, from latent infection to active disease, exists within a continuous spectrum of metabolic bacterial activity and antagonistic immunological responses.
    explanation: This indicates the variable duration of progression from latent to active TB, supporting the statement.
  - reference: PMID:37094782
    reference_title: "Duration of Symptoms Prior to Pediatric and Adolescent Tuberculosis Diagnosis and Its Impact on Schooling in Tanzania: A Mixed Methods Study."
    supports: SUPPORT
    snippet: 'In this cohort, children and adolescents diagnosed with TB experienced symptoms for a median of 85 days (interquartile range: 30, 231 days) prior to treatment initiation.'
    explanation: The variable duration of symptom onset supports the statement.
  - reference: PMID:35704248
    reference_title: "Transmission Dynamics of Tuberculosis with Age-specific Disease Progression."
    supports: SUPPORT
    snippet: The system considers demographic structure coupling with the continuous development of disease stage, which is crucial for studying how aging affects tuberculosis dynamics and disease progression.
    explanation: This implies that TB progression has a variable duration depending on individual factors like age.
pathophysiology:
- name: Phagocytosis
  description: Mycobacterium tuberculosis is engulfed by alveolar macrophages but resists destruction, leading to granuloma formation.
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: T Cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  biological_processes:
  - preferred_term: type I interferon signaling pathway
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
  - preferred_term: phagosome maturation
    term:
      id: GO:0090382
      label: phagosome maturation
  downstream:
  - target: GBP4-Mediated Autophagy-Dependent TB Restriction
    description: Phagocytosis of M. tuberculosis triggers type I interferon signaling, which induces GBP4 expression as a host-directed restriction mechanism.
    evidence:
    - reference: PMID:42501331
      reference_title: "Human GBP4 promotes TRIM21-BIP-dependent autophagy to restrict M. tuberculosis infection by preventing SORT1-mediated progranulin degradation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Interferons (IFNs) are potent antimicrobial cytokines... guanylate-binding proteins (GBPs) are IFN-inducible"
      explanation: Demonstrates that GBP4 is induced as an IFN-responsive effector during TB infection.
  - target: Granuloma Formation
    description: Infected macrophages differentiate into foamy macrophages which form the cellular core of TB granulomas.
  evidence:
  - reference: PMID:14745511
    reference_title: "Macrophage response to Mycobacterium tuberculosis infection."
    supports: SUPPORT
    snippet: The immune response to Mycobacterium tuberculosis (Mtb) infection is the formation of multicellular lesions, or granolomas, in the lung of the individual
    explanation: This reference supports the claim that Mycobacterium tuberculosis infection leads to granuloma formation.
  - reference: PMID:30306257
    reference_title: "Macrophage-microbe interaction: lessons learned from the pathogen Mycobacterium tuberculosis."
    supports: SUPPORT
    snippet: Phagocytosis refers to the process of internalization and degradation of particulate material... One microbe that is particularly successful at surviving within macrophages is the pathogen Mycobacterium tuberculosis, which can efficiently manipulate the macrophage at several levels, including modulation of the phagocytic pathway as well as interfering with a number of immune activation pathways that normally would lead to eradication of the internalized bacilli.
    explanation: This reference supports the specific involvement of macrophages and the resistance of Mycobacterium tuberculosis to degradation within phagocytes.
  - reference: PMID:2425678
    reference_title: "Role of alveolar macrophage- and lung T cell-derived mediators in pulmonary sarcoidosis."
    supports: SUPPORT
    snippet: The process of granuloma formation in the lung is mediated by an intimate interaction between macrophages and T cells, and this interaction provides the appropriate environment for granuloma formation and the development of fibrosis.
    explanation: While this reference supports the role of macrophages and T cells in granuloma formation, it does not address the specific mechanisms by which Mycobacterium tuberculosis resists destruction.
  - reference: PMID:25607549
    reference_title: "Autophagy in the fight against tuberculosis."
    supports: SUPPORT
    snippet: Upon invading host cells by phagocytosis, M. tuberculosis can replicate within infected cells by arresting the maturation of the phagosome whose function is to target the pathogen for elimination.
    explanation: This reference partially supports the claim by highlighting that M. tuberculosis avoids destruction within host cells, though it does not explicitly mention granuloma formation.
- name: GBP4-Mediated Autophagy-Dependent TB Restriction
  description: Type I interferon-inducible GBP4 (guanylate-binding protein 4) mediates autophagy-dependent restriction of Mycobacterium tuberculosis through a TRIM21-dependent autophagy pathway that prevents SORT1-mediated progranulin degradation. This activates TFEB and FOXO3a, driving lysosomal acidification and phagosome-lysosome fusion to enhance intracellular bacterial killing.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: type I interferon signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
  - preferred_term: autophagy
    modifier: INCREASED
    term:
      id: GO:0006914
      label: autophagy
  - preferred_term: phagosome maturation
    modifier: INCREASED
    term:
      id: GO:0090382
      label: phagosome maturation
  evidence:
  - reference: PMID:42501331
    reference_title: "Human GBP4 promotes TRIM21-BIP-dependent autophagy to restrict M. tuberculosis infection by preventing SORT1-mediated progranulin degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our study uncovers a key role for GBP4 in regulating cell-autonomous resistance in human macrophages and may facilitate the development of host-directed therapies against tuberculosis"
    explanation: This study characterizes GBP4 as a type I IFN-inducible host factor specifically mediating autophagy-dependent TB restriction in human macrophages, a previously incompletely characterized effector mechanism.
- name: Granuloma Formation
  description: Immune cells form a granuloma to contain the infection, but sometimes the bacteria can break out, causing active TB.
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: T Cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: lipid metabolic process
    term:
      id: GO:0006629
      label: lipid metabolic process
  - preferred_term: cholesterol transport
    term:
      id: GO:0030301
      label: cholesterol transport
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Tissue Damage
    description: Granuloma necrosis leads to cavitation and destruction of lung parenchyma.
    evidence:
    - reference: PMID:26758178
      reference_title: "Postprimary Tuberculosis and Macrophage Necrosis: Is There a Big ConNECtion?"
      supports: SUPPORT
      snippet: Adult or postprimary tuberculosis (TB) accounts for most TB cases. Its hallmark is pulmonary cavitation, which occurs as a result of necrosis in the lung in individuals with tuberculous pneumonia.
      explanation: This reference establishes that granuloma necrosis leads to cavitary lung disease and tissue destruction.
  locations:
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:23626591
    reference_title: "Modeling the Mycobacterium tuberculosis Granuloma - the Critical Battlefield in Host Immunity and Disease."
    supports: SUPPORT
    snippet: Granulomas are the hallmark of Mycobacterium tuberculosis (M.tb) infection and thus sit at the center of tuberculosis (TB) immunopathogenesis.
    explanation: This review states granulomas are central to TB immunopathogenesis, supporting granuloma formation as a core mechanism.
  - reference: PMID:14745511
    reference_title: "Macrophage response to Mycobacterium tuberculosis infection."
    supports: SUPPORT
    snippet: The immune response to Mycobacterium tuberculosis (Mtb) infection is the formation of multicellular lesions, or granolomas, in the lung of the individual.
    explanation: The reference describes the formation of granulomas in the lung as part of the immune response to Mtb infection, which aligns with the statement.
  - reference: PMID:28577054
    reference_title: "[What is a granuloma?]."
    supports: SUPPORT
    snippet: The typical composition is a center of macrophages/histiocytes with lymphocytes at the border.
    explanation: The reference indicates the involvement of macrophages and T cells (lymphocytes) in granuloma formation, which supports the statement.
  - reference: PMID:36920308
    reference_title: "Spatial mapping reveals granuloma diversity and histopathological superstructure in human tuberculosis."
    supports: SUPPORT
    snippet: granulomas are pathologically diverse, their tissue-wide heterogeneity has not been spatially resolved at the single-cell level in human tissues.
    explanation: The reference discusses the diversity of granulomas in the lung and their formation in response to TB, which supports the statement.
  - reference: PMID:25319335
    reference_title: "Beyond macrophages: the diversity of mononuclear cells in tuberculosis."
    supports: SUPPORT
    snippet: Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), is an intracellular pathogen of mononuclear phagocytes.
    explanation: While the reference discusses infection of macrophages and various cell types by M. tuberculosis, it doesn't mention T cells and granuloma formation specifically.
  - reference: PMID:33720848
    reference_title: "The Pathology of Lymphocytes, Histiocytes, and Immune Mechanisms in Mycobacterium tuberculosis Granulomas."
    supports: SUPPORT
    snippet: Granuloma formation is the pathologic hallmark of tuberculosis (TB).
    explanation: The reference highlights granuloma formation as a key feature of tuberculosis, supporting the statement.
- name: Neutrophil Activation and NETosis
  description: Type I interferon-linked neutrophil programs drive NET formation contributing to tissue pathology, caseating necrosis, and vascular occlusion in progressive TB.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil degranulation
    term:
      id: GO:0043312
      label: neutrophil degranulation
  - preferred_term: neutrophil extracellular trap formation
    term:
      id: GO:0140645
      label: neutrophil extracellular trap formation
  locations:
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  downstream:
  - target: Tissue Damage
    description: NETs contribute to immunopathology, tissue injury, and relapse risk in TB.
- name: Tissue Damage
  locations:
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  description: Active TB can cause cavitation and destruction of lung tissue.
  evidence:
  - reference: PMID:32482293
    reference_title: "Cavitary tuberculosis: the gateway of disease transmission."
    supports: SUPPORT
    snippet: Cavitation is a dangerous consequence of pulmonary tuberculosis associated with poor outcomes, treatment relapse, higher transmission rates, and development of drug resistance.
    explanation: The reference explicitly mentions cavitation as a severe consequence of pulmonary tuberculosis, which aligns with the statement.
  - reference: PMID:27245780
    reference_title: "Hypoxia and tissue destruction in pulmonary TB."
    supports: SUPPORT
    snippet: Human TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.
    explanation: This reference provides evidence that TB lesions result in hypoxia and enzymatic activity that contributes to the destruction of lung tissue and cavitation.
  - reference: PMID:16136463
    reference_title: "Lung remodeling in pulmonary tuberculosis."
    supports: SUPPORT
    snippet: Pulmonary cavitation with cough-generated aerosol is the principle means of spread, and lung remodeling (healed cavitation, fibrosis, and bronchiectasis) is a major cause of lung disability.
    explanation: This reference discusses the relationship between TB, cavitation, and lung tissue remodeling, underscoring the statement that active TB causes cavitation and tissue damage.
  - reference: PMID:25361920
    reference_title: "Pathogenesis of post primary tuberculosis: immunity and hypersensitivity in the development of cavities."
    supports: SUPPORT
    snippet: After many months, the affected lung suddenly undergoes caseation necrosis with vanishingly few MTB. The necrotic tissue fragments to produce a cavity or hardens to develop fibrocaseous disease.
    explanation: This reference explains the process of caseation necrosis leading to cavity formation in the lung, which supports the statement regarding active TB causing cavitation and tissue destruction.
- name: Drug Resistance Mechanisms
  description: Development of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB through genetic mutations that confer resistance to first-line and second-line antitubercular drugs, driven by ineffective treatment regimens and irregular antibiotic exposure.
  downstream:
  - target: Treatment Failure
    description: Drug-resistant TB strains render standard treatment regimens ineffective, leading to persistent infection and continued disease transmission.
  evidence:
  - reference: PMID:42154079
    reference_title: "Multidrug-resistant tuberculosis: a comprehensive review of pathogenesis, drug resistance, current treatment and future prospects."
    supports: SUPPORT
    snippet: There is also a discussion of the MTB lineage and the mutant types. The mechanisms of multidrug resistance and ineffective treatment regimens have driven advances in drug development and alternative therapeutics.
    explanation: This comprehensive review explicitly addresses the mechanisms of multidrug resistance and the role of mutations in driving treatment failures and the need for novel therapeutics.
- name: Immune Evasion
  description: Mycobacterium tuberculosis employs mechanisms of bacterial pathogenesis to counteract the human defense system, contributing to drug resistance and chronic infection persistence.
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: T Cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: type I interferon signaling pathway
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
  - preferred_term: adaptive immune response
    term:
      id: GO:0002250
      label: adaptive immune response
  evidence:
  - reference: PMID:42154079
    reference_title: "Multidrug-resistant tuberculosis: a comprehensive review of pathogenesis, drug resistance, current treatment and future prospects."
    supports: SUPPORT
    snippet: This comprehensive review introduces the mechanisms of bacterial pathogenesis against the human defence system and the development of drugs against MTB, with particular emphasis on the mechanisms of drug resistance and mutations that render them ineffective globally.
    explanation: This review covers mechanisms by which MTB counteracts the human defense system, supporting pathogen-host immune interactions as a driver of chronic infection.
genetic:
- name: TREM2
  gene_term:
    preferred_term: TREM2
    term:
      id: hgnc:17761
      label: TREM2
  association: Foamy macrophage formation and Mtb persistence
  notes: TREM2-positive macrophages are enriched in alveoli, colocalize with lipid droplets and Mtb antigens, and form permissive niches for bacterial persistence. Mycolic acids and PDIM induce TREM2 expression.
- name: APOE
  gene_term:
    preferred_term: APOE
    term:
      id: hgnc:613
      label: APOE
  association: Lipid metabolism in TB-infected macrophages
  notes: Part of TREM2-positive foamy macrophage signature; mediates lipid trafficking that supports intracellular bacterial niche.
- name: NPC2
  gene_term:
    preferred_term: NPC2
    term:
      id: hgnc:14537
      label: NPC2
  association: Lysosomal cholesterol handling
  notes: Upregulated in foamy macrophages; altered cholesterol transport contributes to lipid droplet accumulation and permissive environment for Mtb.
- name: PLIN2
  gene_term:
    preferred_term: PLIN2
    term:
      id: hgnc:248
      label: PLIN2
  association: Lipid droplet marker in foamy macrophages
  notes: Marks lipid droplets that colocalize with Mtb antigens in alveolar macrophages; indicative of metabolic reprogramming.
- name: LIPA
  gene_term:
    preferred_term: LIPA
    term:
      id: hgnc:6617
      label: LIPA
  association: Lysosomal lipid catabolism
  notes: Lysosomal acid lipase involved in cholesterol ester hydrolysis; dysregulated during Mtb infection contributing to foam cell formation.
- name: TBK1
  gene_term:
    preferred_term: TBK1
    term:
      id: hgnc:11584
      label: TBK1
  association: Type I interferon signaling pathway
  notes: Part of cGAS-STING-TBK1-IRF3 cytosolic DNA sensing pathway activated by ESX-1-mediated phagosomal membrane damage.
- name: IRF3
  gene_term:
    preferred_term: IRF3
    term:
      id: hgnc:6118
      label: IRF3
  association: Interferon regulatory transcription factor
  notes: Downstream of TBK1; drives type I interferon responses that can be both protective and pathogenic depending on timing and magnitude.
- name: GBP4
  gene_term:
    preferred_term: GBP4
    term:
      id: hgnc:20480
      label: GBP4
  association: Type I interferon-inducible autophagy-dependent TB restriction
  notes: Guanylate-binding protein 4 is uniquely among the GBP family (GBP1-5) capable of mediating autophagy-dependent Mycobacterium tuberculosis restriction in human macrophages. Acts via a progranulin-BIP-AKT-TFEB/FOXO3a signaling axis promoting lysosomal acidification and phagosome-lysosome fusion. This represents a host-directed antitubercular mechanism.
phenotypes:
- category: Respiratory
  name: Chronic Cough
  description: Persistent cough lasting more than 3 weeks, often productive with sputum, the cardinal respiratory symptom of pulmonary TB.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:29196066
    reference_title: "Cough Due to TB and Other Chronic Infections: CHEST Guideline and Expert Panel Report."
    supports: SUPPORT
    snippet: Cough is common in pulmonary TB and other chronic respiratory infections.
    explanation: While cough is indeed a common symptom of pulmonary TB, the statement specifically categorizes chronic cough as very frequent, which is partially supported but not explicitly confirmed by the literature.
  - reference: PMID:16131501
    reference_title: "Well defined symptoms are of value in the diagnosis of childhood pulmonary tuberculosis."
    supports: SUPPORT
    snippet: A persistent, non-remitting cough was reported in 15/16 (93.8%) children with tuberculosis.
    explanation: This strongly supports the statement as it shows a high prevalence of a persistent chronic cough in children diagnosed with tuberculosis.
  - reference: PMID:35710915
    reference_title: "Cluster analysis categorizes five phenotypes of pulmonary tuberculosis."
    supports: NO_EVIDENCE
    snippet: Initial microbiologic burdens and radiographic features also varied, including the presence of cavities and bilateral infiltration, which reflect TB-related severity.
    explanation: This phenotype-clustering study describes microbiologic burden and radiographic features but the quoted text does not mention cough, so it does not directly support the chronic cough claim (tagged NO_EVIDENCE); frequency is supported by PMID:16131501.
  phenotype_term:
    preferred_term: Chronic Cough
    term:
      id: HP:0034315
      label: Chronic cough
- category: Systemic
  name: Fever
  description: Low-grade fever typically occurring in the afternoon and evening, often accompanied by chills.
  frequency: FREQUENT
  evidence:
  - reference: PMID:11120618
    reference_title: "Tuberculosis as a cause of recurrent fever of unknown origin."
    supports: SUPPORT
    snippet: We describe three patients with recurrent fever thought to be due to tuberculosis, and review the 14 previously reported cases who fulfil the criteria of recurrent fever for at least 1 month's duration
    explanation: The literature indicates that fever is a frequent symptom associated with tuberculosis.
  - reference: PMID:31641790
    reference_title: "[Tuberculosis]."
    supports: SUPPORT
    snippet: Tuberculosis is a bacterial infectious disease that is usually transmitted by inhalation of droplets containing the bacteria.
    explanation: While this reference does affirm that tuberculosis causes systemic issues, it does not directly specify fever as a frequent phenotype.
  - reference: PMID:18173876
    reference_title: "How good are systemic symptoms and blood inflammatory markers at detecting individuals with tuberculosis?"
    supports: SUPPORT
    snippet: 'SETTING: The diagnosis of tuberculosis (TB) may be rejected in the absence of symptoms such as fever, sweats or weight loss.'
    explanation: This reference notes the association of fever with tuberculosis but also highlights cases where fever may be absent, hence only partially supporting the statement.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
- category: Systemic
  name: Night Sweats
  description: Profuse sweating during sleep requiring change of bedclothes, a classic constitutional symptom of active TB.
  frequency: FREQUENT
  evidence:
  - reference: PMID:31599243
    reference_title: "Tuberculosis in Systemic Lupus Erythematosus Patients."
    supports: SUPPORT
    snippet: Cough, night sweat, fever, anorexia were significant presenting features.
    explanation: The study documents night sweats as a significant symptom in TB patients.
  - reference: PMID:12643362
    reference_title: "Diagnosing night sweats."
    supports: SUPPORT
    snippet: Tuberculosis and lymphoma are diseases in which night sweats are a dominant symptom, but these are infrequently found to be the cause of night sweats in modern practice.
    explanation: While night sweats are a notable symptom of TB, the reference suggests that in modern practice, they are less frequently the cause of night sweats compared to other conditions.
  - reference: PMID:21813327
    reference_title: "Clinical symptoms and microbiological outcomes in tuberculosis treatment trials."
    supports: SUPPORT
    snippet: During therapy, fever, sweats, and dyspnea decreased most rapidly, with near resolution by the end of therapy.
    explanation: The data supports the presence of night sweats as a frequent symptom in TB, with sweats reducing significantly during therapy.
  phenotype_term:
    preferred_term: Night sweats
    term:
      id: HP:0030166
      label: Night sweats
- category: Systemic
  name: Weight Loss
  description: Unintentional weight loss and wasting, giving rise to the historical term "consumption" for TB.
  frequency: FREQUENT
  notes: Also known as consumption historically.
  evidence:
  - reference: PMID:36451280
    reference_title: "Predictors of weight loss during the intensive phase of tuberculosis treatment in patients with drug-susceptible pulmonary tuberculosis in South India."
    supports: SUPPORT
    snippet: Tuberculosis (TB) is well-known for causing wasting. Patients on treatment gain weight and weight loss is associated with unfavorable treatment outcomes.
    explanation: This supports the statement that weight loss is a frequently observed systemic phenotype associated with tuberculosis.
  - reference: PMID:38736083
    reference_title: "Challenges in Diagnosis of Esophageal Tuberculosis."
    supports: SUPPORT
    snippet: Esophageal TB most commonly presents with dysphagia, odynophagia, retrosternal pain, and systemic symptoms like decreased appetite, loss of weight, and low-grade fever as associated or other presentations.
    explanation: This reference supports the statement by indicating that weight loss is a common systemic symptom of esophageal tuberculosis.
  - reference: PMID:23531875
    reference_title: "Tuberculosis in CBA/J mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: CBA/J mice may model these events, as sick mice share features with TB patients, including weight loss...
    explanation: Although the study is on mice, it draws parallels with human TB patients, reinforcing that weight loss is a frequently observed phenotype.
  - reference: PMID:18173876
    reference_title: "How good are systemic symptoms and blood inflammatory markers at detecting individuals with tuberculosis?"
    supports: SUPPORT
    snippet: The diagnosis of tuberculosis (TB) may be rejected in the absence of symptoms such as fever, sweats or weight loss... In our population, TB, including pulmonary disease, frequently presented without fever, sweats or weight loss and with normal blood inflammatory markers.
    explanation: This indicates that while weight loss is a known symptom, it is not always present in all TB cases, suggesting that it may be frequent but not ubiquitous.
  - reference: PMID:8623687
    reference_title: "Outpatient management of tuberculosis."
    supports: SUPPORT
    snippet: All patients with a positive reaction to the tuberculin skin test should be evaluated for weight loss, night sweats, fever, chronic cough and other signs of active tuberculosis.
    explanation: This reference confirms that weight loss is one of the systemic symptoms that are frequently checked for in TB patients.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
- category: Hematologic
  name: Hemoptysis
  description: Coughing up blood or blood-streaked sputum, indicating cavitary disease or erosion into blood vessels.
  frequency: OCCASIONAL
  notes: Coughing up blood.
  evidence:
  - reference: PMID:12816036
    reference_title: "[Hemoptysis]."
    supports: SUPPORT
    snippet: The most common causes of hemoptysis are tuberculosis, lung carcinoma, bronchiectasis but idiopathic forms are frequent.
    explanation: The text states that tuberculosis is one of the most common causes of hemoptysis, supporting the statement.
  phenotype_term:
    preferred_term: Hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis
- category: Respiratory
  frequency: FREQUENT
  name: Chest Pain
  description: Pleuritic chest pain worsening with breathing or coughing, often indicating pleural involvement.
  notes: Often described as pleuritic chest pain
  evidence:
  - reference: PMID:17508531
    reference_title: "Pleurisy."
    supports: SUPPORT
    snippet: Pleuritic chest pain is a common presenting symptom and has many causes, which range from life-threatening to benign, self-limited conditions.
    explanation: The reference mentions pleuritic chest pain as a common symptom, but it does not specifically state that it is frequently associated with tuberculosis.
  - reference: PMID:27499981
    reference_title: "Tuberculous pleural effusion."
    supports: SUPPORT
    snippet: TPE usually presents as an acute illness with fever, cough and pleuritic chest pain.
    explanation: This reference supports the statement as it explicitly mentions that tuberculous pleural effusion (a form of extrapulmonary tuberculosis) commonly presents with pleuritic chest pain.
  - reference: PMID:30762202
    reference_title: "Chest Tuberculosis in Children."
    supports: NO_EVIDENCE
    snippet: Chest is the commonest site of involvement by tuberculosis (TB) in children; lungs being the most frequently affected region, followed by nodes, pleura and chest wall.
    explanation: While this reference does not directly state chest pain, it supports the involvement of the chest in tuberculosis, which can be associated with pleuritic chest pain.
  phenotype_term:
    preferred_term: Chest pain
    term:
      id: HP:0100749
      label: Chest pain
- category: Respiratory
  frequency: OCCASIONAL
  name: Dyspnea
  description: Shortness of breath due to extensive pulmonary involvement, pleural effusion, or fibrosis.
  notes: Shortness of breath
  evidence:
  - reference: PMID:15623010
    reference_title: "Tuberculosis prevention and treatment."
    supports: NO_EVIDENCE
    snippet: Symptoms of pulmonary TB are a cough with or without sputum production lasting at least three weeks, chest pain, hemoptysis, fever, night sweats, weight loss, lack of appetite, chills and weakness.
    explanation: The symptom list quoted here does not include dyspnea/shortness of breath, so this reference does not directly support dyspnea as a tuberculosis symptom (tagged NO_EVIDENCE).
  - reference: PMID:29900887
    reference_title: "Pulmonary functions' assessment in post-tuberculosis cases by spirometry: Obstructive pattern is predominant and needs cautious evaluation in all treated cases irrespective of symptoms."
    supports: SUPPORT
    snippet: Lung function impairment is known to occur after pulmonary TB irrespective of duration of treatment and outcome of disease.
    explanation: This reference indicates that lung function issues, including dyspnea, can persist even after successful treatment of tuberculosis.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
- category: Systemic
  frequency: OCCASIONAL
  name: Fatigue
  description: Persistent tiredness and weakness associated with chronic infection and inflammatory response.
  evidence:
  - reference: PMID:35189895
    reference_title: "How mycobacterium tuberculosis infection could lead to the increasing risks of chronic fatigue syndrome and the potential immunological effects: a population-based retrospective cohort study."
    supports: SUPPORT
    snippet: Patients with chronic fatigue syndrome and post-tuberculosis experience similar symptoms. Furthermore, chronic fatigue syndrome and tuberculosis share similar plasma immunosignatures.
    explanation: The study indicates that tuberculosis can lead to symptoms similar to chronic fatigue syndrome, supporting the statement that fatigue can be a systemic symptom of tuberculosis.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Musculoskeletal
  frequency: OCCASIONAL
  name: Back Pain
  description: Localized spinal pain that may indicate vertebral TB (Pott's disease) with potential neurological complications.
  notes: May indicate spinal tuberculosis (Pott's disease)
  evidence:
  - reference: PMID:16882280
    reference_title: "Spinal tuberculosis: overlooked?"
    supports: SUPPORT
    snippet: The findings of this study indicate that TB is a common cause of LBP that is liable to be overlooked in the differential diagnosis of LBP.
    explanation: The study indicates that tuberculosis is a common cause of low back pain (LBP), supporting the statement that back pain may indicate spinal tuberculosis.
  - reference: PMID:29358061
    reference_title: "Pott's Disease Resulting in Complete Cervical Vertebral Destruction."
    supports: SUPPORT
    snippet: We present a case report of a military veteran presenting with neck pain and initially diagnosed with cervical disc disease. The patient's pain progressed to the point of developing paresthesias in his bilateral upper extremities. Eventually, cervical spine radiographs were obtained that revealed complete cervical vertebral body destruction from spinal tuberculosis.
    explanation: This case report supports the statement that back pain may indicate spinal tuberculosis, as it describes a patient whose neck pain was eventually diagnosed as spinal tuberculosis.
  - reference: PMID:19845697
    reference_title: "Osteoarticular tuberculosis in Tehran, Iran: a 2-year study."
    supports: SUPPORT
    snippet: In TB spondylitis, the lumbar (22.7%) and thoracic (50%) vertebrae were the most commonly involved sites.
    explanation: This study supports the statement by indicating that the lumbar and thoracic vertebrae are commonly involved in TB spondylitis, which can manifest as back pain.
  - reference: PMID:33393654
    reference_title: "Pott disease: when lumbar pain is not innocent."
    supports: SUPPORT
    snippet: In this article, we present a rare case of progressed tuberculous infection involving the respiratory and musculoskeletal system in a 36-year-old patient whose main complaints were non-specific and mild, and started only two weeks before his diagnosis, despite the advanced disease.
    explanation: This case supports the statement by illustrating that tuberculosis can involve the musculoskeletal system, presenting as back pain.
  phenotype_term:
    preferred_term: Back Pain
    term:
      id: HP:0003418
      label: Back pain
- category: Lymphatic
  frequency: OCCASIONAL
  name: Lymphadenopathy
  description: Enlarged lymph nodes, particularly cervical, often cold and matted, indicating extrapulmonary TB.
  notes: Swollen lymph nodes, especially in the neck
  evidence:
  - reference: PMID:30513392
    reference_title: "Tuberculous neck lymphadenopathy: A diagnostic challenge."
    supports: SUPPORT
    snippet: TB can affect most organs in the head and neck region, such as the lymph nodes, larynx, middle ear, oral cavity and pharynx. In particular, as for cervical tuberculosis lymphadenopathy, a predominant involvement of the posterior triangle, supraclavicular, and internal jugular group of nodes bilaterally can be observed.
    explanation: The literature supports that tuberculosis can cause lymphadenopathy, specifically in the neck region, but it does not provide a clear indication of frequency.
  - reference: PMID:38317037
    reference_title: "Lymphoma and Other Lymph Node Pathologies Among Adult Patients with Lymphadenopathy in Abakaliki, Nigeria."
    supports: SUPPORT
    snippet: Other major causes of lymphadenopathy were metastatic tumor deposits, reactive lymphoid hyperplasia, and tuberculous lymphadenitis.
    explanation: The literature indicates that tuberculous lymphadenitis is one of the major causes of lymphadenopathy, but it does not specify how frequently this occurs.
  - reference: PMID:37743370
    reference_title: "Magnitude of tuberculosis lymphadenitis, risk factors, and rifampicin resistance at Adama city, Ethiopia: a cross-sectional study."
    supports: SUPPORT
    snippet: Close to half of patients with enlarged lymph nodes were positive for M. tuberculosis by the GeneXpert method in the study area.
    explanation: The study shows a significant prevalence of TB lymphadenitis among patients with enlarged lymph nodes, but it does not provide a frequency classification such as 'occasional'.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
biochemical:
- name: Tuberculin Skin Test (TST)
  presence: Positive
  notes: Indicates TB infection, not necessarily active disease.
  evidence:
  - reference: PMID:25440529
    reference_title: "Tuberculin skin test positivity without tuberculosis contact: A major challenge in childhood."
    supports: SUPPORT
    snippet: Worldwide, tuberculin skin tests (TSTs) commonly give false positive results for those who had been given the Bacillus-Calmette-Guerin vaccine such as is routinely administered in Turkey.
    explanation: While mentioning the possibility of false positives due to BCG vaccination, the reference acknowledges that positive TST results primarily indicate TB infection.
- name: Interferon-Gamma Release Assay (IGRA)
  presence: Positive
  notes: Blood test indicating TB infection.
  evidence:
  - reference: PMID:28220979
    reference_title: "More significance of TB-IGRA except for the diagnose of tuberculosis."
    supports: SUPPORT
    snippet: TB-IGRA results were in positive proportion to the lymphocytes, CD4(+) T cells and CD4(+) CD28(+) T cells, whereas negative to the Treg cells.
    explanation: This study discusses the positive TB-IGRA test results in patients infected with tuberculosis, supporting the statement that a positive IGRA indicates TB infection.
  - reference: PMID:26018533
    reference_title: "Gamma Interferon Assays Used in the Diagnosis of Tuberculosis."
    supports: SUPPORT
    snippet: Recently, two new diagnostic tests have been introduced; these two new tests can detect TB infection in patients by challenging peripheral blood cells with specific TB proteins.
    explanation: The abstract confirms that the Interferon-Gamma Release Assay (IGRA) is a blood test used to detect TB infection.
  - reference: PMID:33276277
    reference_title: "Optimized interferon-gamma release assays for detection of Mycobacterium bovis infection in African buffaloes (Syncerus caffer)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Accurate and early detection of M. bovis infection in buffaloes is important for controlling transmission. Assays that detect cell-mediated immune responses to M. bovis in buffaloes have been developed although these often display suboptimal sensitivity or specificity.
    explanation: This study discusses IGRA as a diagnostic tool for detecting TB infections, supporting the claim.
  - reference: PMID:34049606
    reference_title: "Interferon-gamma release assays for latent tuberculosis infection screening in Canadian federal correctional facilities."
    supports: SUPPORT
    snippet: We observed concordance between TST and QFT-GIT in 90 of 306 (29.4%) inmates. Persons with TST+/QFT-GIT+ results were less likely to be male (OR 3.94, 95% CI 1.73-8.97) or have a BCG vaccination history (OR 0.34, 95% CI 0.12-0.95), and more likely to be foreign-born (P < 0.001).
    explanation: This study shows that the QuantiFERON-TB Gold In-Tube assay (a type of IGRA) is used to detect TB infection, supporting the claim.
  - reference: PMID:34270559
    reference_title: "Mycobacterial heparin-binding hemagglutinin (HBHA)-induced interferon-γ release assay (IGRA) for discrimination of latent and active tuberculosis: A systematic review and meta-analysis."
    supports: SUPPORT
    snippet: The HBHA-IGRA is a promising immunodiagnostic test for discrimination of latent and active TB, which can be added in commercial IGRAs to enhance the differential diagnostic performance.
    explanation: The abstract draws on the efficiency of IGRA in distinguishing between latent and active TB, supporting the claim that IGRA is related to TB detection.
diagnosis:
- name: Sputum Microscopy
  description: Microscopic examination of sputum samples stained with Ziehl-Neelsen or auramine to identify acid-fast bacilli.
  presence: Positive
  notes: Detection of acid-fast bacilli.
  evidence:
  - reference: PMID:30054578
    reference_title: "Automatic microscopic detection of mycobacteria in sputum: a proof-of-concept."
    supports: SUPPORT
    snippet: We developed and evaluated an operator-independent microscopic examination of sputum smears for the automated detection and enumeration of acid-fast bacilli using a ZEISS Axio Scan.Z1 microscope.
    explanation: The study supports that sputum microscopy can detect acid-fast bacilli. It emphasizes an automated method but still aligns with the use of sputum microscopy for diagnosis.
  - reference: PMID:15535337
    reference_title: "Pulmonary tuberculosis--a review of clinical features and diagnosis in 232 cases."
    supports: SUPPORT
    snippet: Sputum direct smear was positive for acid-fast bacilli in only 22.8% of patients and 11.2% were diagnosed base on positive sputum culture
    explanation: This study confirms that sputum microscopy can detect acid-fast bacilli, but it also highlights instances where sputum may be negative even in TB patients.
  - reference: PMID:27847013
    reference_title: "Fluorescein diacetate vital staining for detecting viability of acid-fast bacilli in patients on antituberculosis treatment."
    supports: SUPPORT
    snippet: Of the 100 ZN positive specimens, 74 were FDA positive of which 70 were reported positive by both the readers.
    explanation: Sputum microscopy positivity for acid-fast bacilli is mentioned but the study's focus is on the FDA staining method.
  - reference: PMID:10734523
    reference_title: "Diagnosis of tuberculosis in sputum negative patients in Dar es Salaam."
    supports: SUPPORT
    snippet: Forty three (24.2%) were sputum smear positive for acid fast bacilli (AAFB).
    explanation: The study supports sputum microscopy for TB diagnosis but only in 24.2% of cases verified by smear.
  - reference: PMID:35180496
    reference_title: "Concentrated specimen smear microscopy utilising a polymer membrane sandwich filtration vessel for the detection of acid-fast bacilli in health facilities in Sabah, East Malaysia."
    supports: SUPPORT
    snippet: The SFV-CSSM showed higher sensitivity than DSSM (79.4% versus 60.5%) and less background interference.
    explanation: The study supports sputum microscopy but highlights an advanced method with higher sensitivity.
  - reference: PMID:21333111
    reference_title: "Implementation of liquid culture for tuberculosis diagnosis in a remote setting: lessons learned."
    supports: SUPPORT
    snippet: Although sputum smear microscopy is the primary method for tuberculosis (TB) diagnosis in low-resource settings, it has low sensitivity.
    explanation: Sputum microscopy is acknowledged as the primary method but with limitations in sensitivity.
- name: Chest X-Ray
  description: Radiographic imaging to identify pulmonary infiltrates, cavitations, and hilar lymphadenopathy characteristic of TB.
  notes: Shows cavitary lesions and other signs of active pulmonary TB.
  evidence:
  - reference: PMID:24429302
    reference_title: "Chronic inactive pulmonary tuberculosis and treatment sequelae: chest radiographic features."
    supports: SUPPORT
    snippet: The chest radiograph (CXR) is a key initial tool in the diagnosis of many lung conditions, including pulmonary tuberculosis (TB). With proper use of anti-tuberculosis drugs, TB can be treated effectively and many CXR changes are limited.
    explanation: This reference establishes that chest radiographs (CXRs) are key tools in diagnosing pulmonary tuberculosis, supporting the statement that chest X-ray is used in the diagnosis of TB.
  - reference: PMID:37977833
    reference_title: "Pulmonary tuberculosis presenting with cluster sign and galaxy sign."
    supports: SUPPORT
    snippet: Follow-up CT showed CS progressing to a cavitatory shadow and GS intensification. The detection of Mycobacterium tuberculosis (M. tuberculosis) in a subsequent sputum analysis prompted treatment with antitubercular drugs, leading to symptom relief.
    explanation: This reference supports the statement regarding the use of chest X-rays in diagnosing TB as it discusses how chest CT (an advanced form of X-ray) shows cavitary lesions, which are indicative of active pulmonary TB.
  - reference: PMID:8553964
    reference_title: "Laryngeal tuberculosis: CT findings."
    supports: SUPPORT
    snippet: Radiographic findings consistent with active pulmonary TB were present in all patients.
    explanation: This reference reinforces the use of radiographic imaging (including chest X-rays) in identifying active pulmonary TB.
  - reference: PMID:26634258
    reference_title: "Evaluation of Chest X-ray and Thoracic Computed Tomography in Patients with Suspected Tuberculosis."
    supports: SUPPORT
    snippet: Evaluation for pulmonary TB in children with positive isolated TSTs should be made primarily with PA chest X-ray.
    explanation: This further supports the statement by emphasizing that chest X-rays (PA chest X-ray) are a primary diagnostic tool for evaluating pulmonary TB.
- name: Sputum Culture
  description: Growth of Mycobacterium tuberculosis on solid or liquid media, the gold standard for diagnosis.
  presence: Positive
  notes: Confirms TB diagnosis.
  evidence:
  - reference: PMID:10970761
    reference_title: "Immunologic diagnosis of tuberculosis: a review."
    supports: SUPPORT
    snippet: However, the sensitivity of sputum smear for acid-fast bacteria is only approximately 50% and sputum culture has a relatively long turnaround time.
    explanation: While sputum culture is considered important for TB diagnosis, it has limitations such as long turnaround time which may affect its utility in confirming TB diagnosis promptly.
  - reference: PMID:31666021
    reference_title: "Viable Mycobacterium tuberculosis in sputum after pulmonary tuberculosis cure."
    supports: SUPPORT
    snippet: Pulmonary tuberculosis (TB) with detectable Mycobacterium tuberculosis in the sputum is a major source of transmission.
    explanation: Although this article acknowledges the importance of sputum smear for transmission evaluation, it also highlights that viable bacteria may still be present in some 'cured' patients, indicating a limitation in using sputum alone for confirming cure.
  - reference: PMID:32755530
    reference_title: "Molecular detection of Mycobacterium tuberculosis in poor-quality cough specimens."
    supports: SUPPORT
    snippet: Poor-quality cough specimens (n=61) from presumptive tuberculosis cases were cultured and GeneXpert MTB/RIF (Xpert) successfully performed on samples transferred by flocked swab into PrimeStore molecular transport medium (PS-MTM). Mycobacterium tuberculosis was grown in culture from 13 (21.3 %).
    explanation: Supports the idea that sputum culture can confirm TB diagnosis, even from poor-quality specimens.
  - reference: PMID:8758132
    reference_title: "Sputum induction for the diagnosis of tuberculosis."
    supports: SUPPORT
    snippet: Confirmation of tuberculosis in young children is difficult as they seldom expectorate sputum... Mycobacterium tuberculosis was cultured from three of them.
    explanation: Indicates that sputum culture is a useful method for confirming TB diagnosis.
  - reference: PMID:27727131
    reference_title: "Culture is an imperfect and heterogeneous reference standard in pediatric tuberculosis."
    supports: SUPPORT
    snippet: Culture, the accepted reference standard for pediatric TB diagnostics, has a low and variable yield that impacts how diagnostic studies should be reported as well as everyday clinical care.
    explanation: While culture is a standard for pediatric TB diagnostics, the low yield suggests it might not confirm all cases.
  - reference: PMID:34397866
    reference_title: "Comparison of chest computed tomography features between pulmonary tuberculosis patients with culture-positive and culture-negative sputum for non-mycobacteria: A retrospective observational study."
    supports: NO_EVIDENCE
    snippet: Patients with a positive culture for non-mycobacteria were significantly older and had lower levels of physical activity...
    explanation: This study focuses on non-mycobacterial cultures and does not specifically address the role of sputum culture in TB diagnosis.
treatments:
- name: Isoniazid
  description: First-line antibiotic for TB treatment.
  notes: It's important to note that resistance to isoniazid can develop through mutations in the katG gene, which reduces the activation of the drug, or in the inhA gene, which decreases the binding affinity of the activated drug to the InhA enzyme. To minimize the risk of resistance, isoniazid is typically used in combination with other antitubercular drugs, such as rifampicin, ethambutol, and pyrazinamide.
  mechanism:
  - name: Prodrug Activation
    description: Isoniazid is a prodrug that requires activation by the bacterial enzyme catalase-peroxidase (KatG). KatG couples the isonicotinic acyl with NADH to form an isonicotinic acyl-NADH complex.
  - name: Inhibition of InhA
    description: The activated form of isoniazid binds to and inhibits the enoyl-acyl carrier protein reductase (InhA), an enzyme involved in the fatty acid synthase II (FAS-II) pathway. This pathway is essential for the synthesis of mycolic acids.
  - name: Depletion of mycolic acids
    description: By inhibiting InhA, isoniazid prevents the synthesis of mycolic acids, which are long-chain fatty acids that make up a significant portion of the mycobacterial cell wall. Mycolic acids provide structural integrity and help the bacteria resist the host's immune response.
  - name: Cell wall disruption
    description: The depletion of mycolic acids leads to the weakening and disruption of the bacterial cell wall. This makes the bacteria more susceptible to the host's immune defenses and other antibiotics.
  - name: Reactive oxygen species
    description: In addition to inhibiting mycolic acid synthesis, the isoniazid-NAD adduct can also generate reactive oxygen species (ROS) and nitric oxide (NO) within the bacteria. These reactive species can cause damage to various bacterial components, including DNA, proteins, and lipids, contributing to the bactericidal effect.
  - name: Bactericidal action
    description: The combination of cell wall disruption and the production of reactive oxygen and nitrogen species ultimately leads to the death of the M. tuberculosis bacteria.
  evidence:
  - reference: PMID:33106268
    reference_title: "Acetylation of Isoniazid Is a Novel Mechanism of Isoniazid Resistance in Mycobacterium tuberculosis."
    supports: SUPPORT
    snippet: Isoniazid (INH), one of the first-line drugs used for the treatment of tuberculosis, is a prodrug which is activated by the intracellular KatG enzyme of Mycobacterium tuberculosis.
    explanation: The description of Isoniazid as a first-line antibiotic for TB treatment and its activation by the KatG enzyme is supported. This aligns with the provided mechanism of prodrug activation.
  - reference: PMID:12164478
    reference_title: "Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis."
    supports: SUPPORT
    snippet: The drugs shown to inhibit mycolic acid biosynthesis are isoniazid, ethionamide, isoxyl, thiolactomycin, and triclosan.
    explanation: The inhibition of mycolic acid biosynthesis by Isoniazid aligns with the described mechanism of action in the statement.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: isoniazid
      term:
        id: CHEBI:6030
        label: isoniazide
- name: Rifampicin
  description: Bactericidal antibiotic used for TB treatment.
  notes: Rifampicin is a broad-spectrum antibiotic that is particularly effective against mycobacteria, including M. tuberculosis, as it can easily penetrate the lipid-rich cell wall.
  mechanism:
  - name: Inhibition of bacterial RNA polymerase
    description: Rifampicin binds to the beta subunit of DNA-dependent RNA polymerase, preventing the initiation of RNA synthesis.
  - name: Disruption of bacterial transcription
    description: By inhibiting RNA polymerase, rifampicin disrupts bacterial transcription, which is essential for protein synthesis and bacterial survival.
  evidence:
  - reference: PMID:11290327
    reference_title: "Structural mechanism for rifampicin inhibition of bacterial rna polymerase."
    supports: SUPPORT
    snippet: Rifampicin (Rif) is one of the most potent and broad spectrum antibiotics against bacterial pathogens and is a key component of anti-tuberculosis therapy, stemming from its inhibition of the bacterial RNA polymerase (RNAP).
    explanation: This reference explains that Rifampicin is a key component of anti-tuberculosis therapy due to its inhibition of bacterial RNA polymerase.
  - reference: PMID:27553018
    reference_title: "Tuberculosis and its Treatment: An Overview."
    supports: SUPPORT
    snippet: For the treatment of TB, administration of multiple antibiotics such as isoniazid, rifampicin, pyrazinamide and ethambutol is required for a long period of time to kill bacteria.
    explanation: This reference confirms that rifampicin is used for the treatment of TB.
  - reference: PMID:34400805
    reference_title: "Rifamycin antibiotics and the mechanisms of their failure."
    supports: SUPPORT
    snippet: Rifamycins exhibit bactericidal activity against many Gram-positive and Gram-negative bacteria by inhibiting RNA polymerase (RNAP).
    explanation: This reference supports the statement by confirming that Rifamycins, including rifampicin, exhibit bactericidal activity by inhibiting RNA polymerase.
  - reference: PMID:33199626
    reference_title: "The antibiotic sorangicin A inhibits promoter DNA unwinding in a Mycobacterium tuberculosis rifampicin-resistant RNA polymerase."
    supports: SUPPORT
    snippet: Rif targets the enzyme RNA polymerase (RNAP).
    explanation: This reference affirms the mechanism of rifampicin targeting RNA polymerase, which validates its use in TB treatment.
  - reference: PMID:28803492
    reference_title: "Rifampin vs. rifapentine: what is the preferred rifamycin for tuberculosis?"
    supports: SUPPORT
    snippet: Rifamycin antibiotics, like rifampin and rifapentine, have unique sterilizing activity against M.tb.
    explanation: This reference supports the use of rifampicin (a Rifamycin antibiotic) for TB treatment due to its sterilizing activity against Mycobacterium tuberculosis.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rifampicin
      term:
        id: CHEBI:28077
        label: rifampicin
- name: Ethambutol
  description: Bacteriostatic antibiotic used for TB treatment.
  notes: Ethambutol is specific to mycobacteria and is often used in combination with other antitubercular drugs to prevent the emergence of drug resistance.
  mechanism:
  - name: Inhibition of arabinogalactan synthesis
    description: Ethambutol interferes with the biosynthesis of arabinogalactan, a key component of the mycobacterial cell wall.
  - name: Inhibition of arabinosyl transferase
    description: Ethambutol inhibits the enzyme arabinosyl transferase, which is responsible for the polymerization of arabinose into arabinan, a precursor of arabinogalactan.
  - name: Compromised cell wall integrity
    description: By disrupting the synthesis of arabinogalactan, ethambutol compromises the integrity of the cell wall, making the bacteria more susceptible to host defenses and other antibiotics.
  evidence:
  - reference: PMID:16209089
    reference_title: "The effect of ethambutol on mycobacterial cell wall permeability to hydrophobic compounds."
    supports: SUPPORT
    snippet: Ethambutol (EMB), the first line drug in the treatment of tuberculosis, is an inhibitor of the biosynthesis of the cell wall compound - arabinogalactan.
    explanation: The literature states that ethambutol interferes with the biosynthesis of arabinogalactan, supporting the mechanism described in the statement.
  - reference: PMID:9949810
    reference_title: "Mechanisms for isoniazid action and resistance."
    supports: SUPPORT
    snippet: Isoniazid is the most widely used antituberculosis drug.
    explanation: The statement specifies ethambutol as a bacteriostatic antibiotic used for TB treatment, whereas this reference talks about isoniazid. It is partially relevant since ethambutol is also an antituberculosis drug, but this reference does not fully address ethambutol's function.
  - reference: PMID:37289062
    reference_title: "Wollamide Cyclic Hexapeptides Synergize with Established and New Tuberculosis Antibiotics in Targeting Mycobacterium tuberculosis."
    supports: SUPPORT
    snippet: In combination with TB antibiotics, wollamide B1 synergistically enhances the activity of several antibiotics... and wollamide B1 did not compromise the antimycobacterial activity of the isoniazid/rifampicin/ethambutol combination.
    explanation: This reference confirms that ethambutol is used in combination with other antitubercular drugs, aligning with the notes in the statement about preventing the emergence of drug resistance.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ethambutol
      term:
        id: CHEBI:4877
        label: ethambutol
- name: Drug-Resistant TB Regimen (BPaL/BPaLM)
  description: All-oral 6-month regimen of bedaquiline, pretomanid, and linezolid, with moxifloxacin added (BPaLM) for fluoroquinolone-susceptible disease, now recommended as first-line therapy for multidrug-resistant / rifampin-resistant TB in place of older 15-month-or-longer injectable-containing regimens.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: bedaquiline
      term:
        id: CHEBI:72292
        label: bedaquiline
    - preferred_term: linezolid
      term:
        id: CHEBI:63607
        label: linezolid
    - preferred_term: moxifloxacin
      term:
        id: CHEBI:63611
        label: moxifloxacin
  evidence:
  - reference: PMID:40693952
    reference_title: "Updates on the Treatment of Drug-Susceptible and Drug-Resistant Tuberculosis: An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Drug-resistant TB recommendation updates include the use of novel regimens containing bedaquiline, pretomanid, and linezolid with or without moxifloxacin."
    explanation: The 2025 ATS/CDC/ERS/IDSA guideline updates drug-resistant TB treatment to the all-oral bedaquiline/pretomanid/linezolid (with or without moxifloxacin) regimens.
  - reference: PMID:40693952
    reference_title: "Updates on the Treatment of Drug-Susceptible and Drug-Resistant Tuberculosis: An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We recommend BPaLM as the first line for MDR/RR-TB without fluoroquinolone resistance or intolerance."
    explanation: The guideline gives a strong recommendation for BPaLM as first-line therapy for multidrug-resistant / rifampin-resistant TB lacking fluoroquinolone resistance.
- name: Directly Observed Therapy (DOT)
  description: Health worker observes and records patients taking their medication to ensure adherence.
  evidence:
  - reference: PMID:17943789
    reference_title: "Directly observed therapy for treating tuberculosis."
    supports: SUPPORT
    snippet: Directly observed therapy (DOT), which involves people directly observing patients taking their antituberculous drugs.
    explanation: The abstract clearly states that DOT involves someone directly observing patients taking their antituberculous drugs to ensure adherence.
  - reference: PMID:29461901
    reference_title: "Predicting treatment outcome of drug-susceptible tuberculosis patients using machine-learning models."
    supports: SUPPORT
    snippet: The World Health Organization (WHO) propagates Directly Observed Therapy Short-course (DOTS) as an effective way to stop the spread of TB in communities with a high burden.
    explanation: The abstract indicates that DOTS is endorsed by WHO as a method to ensure patients adhere to TB treatment.
  - reference: PMID:28410705
    reference_title: "Patients' perception towards directly observed treatment - A qualitative study from Kollam district, Kerala, southern India."
    supports: SUPPORT
    snippet: A flexible, patient centered approach were a family member can act as the DOT provider with guidance from a trained health worker was evolved as the most acceptable and comfortable mode of treatment to majority of the TB patients
    explanation: The abstract reinforces the involvement of a health worker in observing DOT, even if it's flexible to involve family members.
  - reference: PMID:27598709
    reference_title: "A New Method to Directly Observe Tuberculosis Treatment: Skype Observed Therapy, a Patient-Centered Approach."
    supports: SUPPORT
    snippet: To best ensure compliance, directly observed therapy (DOT) is considered the standard of practice.
    explanation: Emphasizes DOT as a standard practice to ensure compliance by observing the patient directly.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Latent TB Treatment
  description: Isoniazid or rifapentine used to prevent latent TB from becoming active.
  evidence:
  - reference: PMID:29910114
    reference_title: "Isoniazid-Rifapentine for Latent Tuberculosis Infection: A Systematic Review and Meta-analysis."
    supports: SUPPORT
    snippet: The 3-month isoniazid-rifapentine regimen is as safe and effective as other recommended latent tuberculosis infection regimens and achieves significantly higher treatment completion rates.
    explanation: This source supports the statement mentioning that a regimen of isoniazid and rifapentine is used for latent TB infection.
  - reference: PMID:19496388
    reference_title: "Identification and management of latent tuberculosis infection."
    supports: SUPPORT
    snippet: The treatment of choice for LTBI is isoniazid for nine months.
    explanation: This source supports the use of isoniazid for the prevention of latent tuberculosis infection (LTBI).
  - reference: PMID:32551948
    reference_title: "Isoniazid Preventive Therapy in Contacts of Multidrug-Resistant Tuberculosis."
    supports: SUPPORT
    snippet: The World Health Organization recommends the use of isoniazid (INH) alone or in combination with rifapentine to treat latent tuberculosis infections.
    explanation: This supports the statement by specifying that WHO recommends isoniazid and rifapentine for the treatment of latent tuberculosis infections.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Host-Directed Therapy
  description: Adjunctive strategies to enhance autophagy, modulate inflammasome activity, or reprogram macrophage lipid metabolism alongside standard antibiotics.
  notes: Emerging therapeutic approaches include autophagy inducers, anti-inflammatory agents targeting excessive NET formation or inflammasome activation, and lipid metabolism modulators to limit foamy macrophage formation and bacterial persistence.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: SQ109
  description: Investigational ethylenediamine compound being explored for activity against drug-resistant M. tuberculosis, derived from ethambutol pharmacophore development.
  notes: Proposed mechanism involves inhibition of MmpL3 (mycobacterial membrane protein Large 3), a trehalose monomycolate flippase required for mycobacterial cell wall biosynthesis. Chemically distinct from bedaquiline (a diarylquinoline) — SQ109 is N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: SQ109
      term:
        id: CHEBI:188155
        label: SQ109(1+)
  evidence:
  - reference: PMID:42154079
    reference_title: "Multidrug-resistant tuberculosis: a comprehensive review of pathogenesis, drug resistance, current treatment and future prospects."
    supports: SUPPORT
    snippet: New molecules that can potentially disarm MTB have been explored, including SQ109, GuaB2, Q203, Largazole, and Auranofin.
    explanation: Novel compound identified as having potential to address MTB drug resistance.
- name: GuaB2
  description: Inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH, encoded by guaB2) in M. tuberculosis, a validated drug target essential for guanine nucleotide biosynthesis.
  notes: Emerging target-based therapeutic explored for activity against MTB.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:42154079
    reference_title: "Multidrug-resistant tuberculosis: a comprehensive review of pathogenesis, drug resistance, current treatment and future prospects."
    supports: SUPPORT
    snippet: New molecules that can potentially disarm MTB have been explored, including SQ109, GuaB2, Q203, Largazole, and Auranofin.
    explanation: Novel compound identified as having potential to address MTB drug resistance.
- name: Q203
  description: Emerging TB drug candidate (telacebec) being explored for activity against multidrug-resistant and extensively drug-resistant TB.
  notes: Proposed mechanism involves targeting the cytochrome bc1 complex (QcrB subunit) of the mycobacterial respiratory chain, distinct from traditional first-line drug targets.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:42154079
    reference_title: "Multidrug-resistant tuberculosis: a comprehensive review of pathogenesis, drug resistance, current treatment and future prospects."
    supports: SUPPORT
    snippet: New molecules that can potentially disarm MTB have been explored, including SQ109, GuaB2, Q203, Largazole, and Auranofin.
    explanation: Novel compound identified as having potential to address MTB drug resistance.
- name: Largazole
  description: Cyclodepsipeptide natural product (histone deacetylase inhibitor) with potential antimycobacterial activity being explored as a novel TB therapeutic.
  notes: Natural product-derived compound in development for TB treatment.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: largazole
      term:
        id: CHEBI:212400
        label: Largazole
  evidence:
  - reference: PMID:42154079
    reference_title: "Multidrug-resistant tuberculosis: a comprehensive review of pathogenesis, drug resistance, current treatment and future prospects."
    supports: SUPPORT
    snippet: New molecules that can potentially disarm MTB have been explored, including SQ109, GuaB2, Q203, Largazole, and Auranofin.
    explanation: Novel compound identified as having potential to address MTB drug resistance.
- name: Auranofin
  description: Gold-containing compound (originally approved for rheumatoid arthritis) being explored for antimycobacterial activity in repurposing programs for TB treatment, particularly in drug-resistant cases.
  notes: Proposed antimycobacterial mechanism involves thioredoxin reductase inhibition. Approved for rheumatoid arthritis; repurposing rationale stems from its novel chemical composition relative to traditional antibiotics.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: auranofin
      term:
        id: CHEBI:2922
        label: auranofin
  evidence:
  - reference: PMID:42154079
    reference_title: "Multidrug-resistant tuberculosis: a comprehensive review of pathogenesis, drug resistance, current treatment and future prospects."
    supports: SUPPORT
    snippet: New molecules that can potentially disarm MTB have been explored, including SQ109, GuaB2, Q203, Largazole, and Auranofin.
    explanation: Novel compound identified as having potential to address MTB drug resistance.
- name: Natural Compound Therapy
  description: Exploration of natural compounds as adjunctive or alternative approaches for TB treatment.
  notes: Includes plant-derived and natural product-based therapeutic strategies.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:42154079
    reference_title: "Multidrug-resistant tuberculosis: a comprehensive review of pathogenesis, drug resistance, current treatment and future prospects."
    supports: SUPPORT
    snippet: natural compounds, bacteriophage therapy, antimicrobial peptides, and probiotics are also explored to help address the global threat posed by MTB.
    explanation: Emerging therapeutic modalities beyond conventional antibiotics being evaluated for TB treatment.
- name: Bacteriophage Therapy
  description: Use of bacteriophages (viruses that infect bacteria) as alternative antimicrobial agents against M. tuberculosis.
  notes: Emerging biotechnology approach for potential TB treatment, particularly relevant for drug-resistant strains.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:42154079
    reference_title: "Multidrug-resistant tuberculosis: a comprehensive review of pathogenesis, drug resistance, current treatment and future prospects."
    supports: SUPPORT
    snippet: natural compounds, bacteriophage therapy, antimicrobial peptides, and probiotics are also explored to help address the global threat posed by MTB.
    explanation: Emerging therapeutic modality being investigated to combat MTB and address antibiotic resistance.
- name: Antimicrobial Peptide Therapy
  description: Use of synthetic or naturally-derived peptides with antimicrobial properties against M. tuberculosis.
  notes: Emerging immunotherapeutic approach leveraging host defense mechanisms.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:42154079
    reference_title: "Multidrug-resistant tuberculosis: a comprehensive review of pathogenesis, drug resistance, current treatment and future prospects."
    supports: SUPPORT
    snippet: natural compounds, bacteriophage therapy, antimicrobial peptides, and probiotics are also explored to help address the global threat posed by MTB.
    explanation: Emerging therapeutic modality being investigated to combat MTB and address antibiotic resistance.
- name: Probiotic Therapy
  description: Use of beneficial microorganisms to enhance immune function and support conventional TB treatment.
  notes: Emerging host-directed therapeutic approach.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:42154079
    reference_title: "Multidrug-resistant tuberculosis: a comprehensive review of pathogenesis, drug resistance, current treatment and future prospects."
    supports: SUPPORT
    snippet: natural compounds, bacteriophage therapy, antimicrobial peptides, and probiotics are also explored to help address the global threat posed by MTB.
    explanation: Emerging therapeutic modality being investigated to combat MTB and address antibiotic resistance.
clinical_trials:
- name: NCT03568383
  phase: PHASE_III
  description: Open-label randomized prophylaxis study comparing delamanid versus isoniazid for preventing active tuberculosis among high-risk household contacts of adults with multidrug-resistant TB over 96 weeks of follow-up.
  evidence:
  - reference: clinicaltrials:NCT03568383
    reference_title: "Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients (PHOENIx MDR-TB)"
    supports: SUPPORT
    snippet: "The purpose of this study is to compare the efficacy and safety of 26 weeks of delamanid (DLM) versus 26 weeks of isoniazid (INH) for preventing confirmed or probable active tuberculosis (TB) during 96 weeks of follow-up among high-risk household contacts (HHCs) of adults with multidrug-resistant tuberculosis (MDR-TB) (index cases)."
    explanation: This trial evaluates delamanid as preventive therapy for household contacts of MDR-TB patients, directly relevant to tuberculosis control strategies.
notes: TB is a significant global health issue, particularly in low-income and developing countries.
disease_term:
  preferred_term: tuberculosis
  term:
    id: MONDO:0018076
    label: tuberculosis
datasets:
- accession: geo:GSE301876
  title: Spatial transcriptomic profiling of alveoli and granuloma regions in patients with active pulmonary tuberculosis
  data_type: SPATIAL_TRANSCRIPTOMICS
  description: Spatial transcriptomic profiling was performed using the GeoMx DSP Whole Transcriptome Atlas to measure expression of over 18,000 genes in alveoli and granuloma core and mantle regions from patients with active pulmonary tuberculosis. Differential gene expression revealed region-specific transcriptional profiles, including signatures related to antimicrobial response and lipid metabolism.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 180
  publication: PMID:40791339
  notes: Identified by GEO DataSets index search for Tuberculosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE296546
  title: 'Diabetes mellitus is associated with a shared hyper-inflammatory immune response in melioidosis and tuberculosis patients: an observational case-control study'
  description: Melioidosis is a serious infection caused by the bacterium Burkholderia pseudomallei (Bp) with a case fatality rate of up to 40% in Northeast Thailand. Diabetes increases the risk of developing melioidosis by 12-fold. A similar, but less marked, relationship with diabetes is seen in tuberculosis (TB) patients, with a 3-fold increased risk of developing TB in people with diabetes. However, the mechanisms underlying increased susceptibility are not fully understood. Whole blood samples of 81 acute melioidosis patients from Northeast Thailand and 151 TB patients from South Africa, Indonesia, Romania and Peru alongside uninfected control cohorts were studied by whole blood RNA sequencing.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 110
  publication: PMID:42318305
  notes: Identified by GEO DataSets index search for Tuberculosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE216985
  title: A unique Mitochondrial Quality Control (MQC) mechanism reverses the phagosome maturation arrest caused by Mycobacterium tuberculosis
  description: Phagosome maturation arrest (PMA) imposed by Mycobacterium tuberculosis (Mtb) is among the classic tools that helps Mtb evade macrophage anti-bacterial response. Here we report a unique crosstalk between mitochondrial quality control (MQC) pathways and the phagosome maturation pathway, which unblocks the PMA and results in the efficient killing of Mtb. Depletion of p62/SQSTM1, a major autophagy adaptor, in human macrophages enhances Mtb killing. However, depletion of p62/SQSTM1 does not impact mitochondrial quality, despite an apparent block in mitophagy flux. Interestingly, in p62KD cells, MQC is ensured via TOM20+-mitochondria-derived vesicles (MDVs).
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 36
  notes: Identified by GEO DataSets index search for Tuberculosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00000000027
  title: WTCCC case-control study for Tuberculosis
  description: WTCCC genome-wide case-control association study for Tuberculosis (TB) using the African samples as controls.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Tuberculosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001001089
  title: Russian GWAS of tuberculosis
  description: Genome-wide association study of cases of tuberculosis from St. Petersburg and Samara, in Russia, compared to healthy controls from the same two cities. Genotyped using the Affy6 platform.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Tuberculosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001001090
  title: GWAS of tuberculosis in Russia
  description: Genome-wide association study of cases of tuberculosis from St Petersburg and Samara, in Russia, compared to healthy controls from the same two cities. Genotype data from Affy6 array.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Tuberculosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: massive:MSV000080238
  title: Mycobacterium tuberculosis normoxia hypoxia reactivation with ActivX-desthiobiotin FP probe
  description: Lysates of Mycobacterium tuberculosis (H37Rv auxotroph mc(2)6020) grown under various conditions (normoxia, hypoxia, reactivation from hypoxia) probed the serine hydrolase probe with ActivX-desthiobiotin FP.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Tuberculosis"). Retrieved 2026-08-02.
- accession: massive:MSV000088254
  title: The Mycobacterium tuberculosis O-phosphorylation landscape
  description: LC-MS/MS tryptic peptide data comprising both label free (phosphoproteome) and TMT10 (global and phosphoproteome) analysis of mycobacterium tuberculosis mutants (WT, GoF, and LoF) grown at stationary phase. Data was searched with MS-GF+ (TMT) and MaxQuant (label free).
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Tuberculosis"). Retrieved 2026-08-02.
- accession: massive:MSV000081205
  title: GeLC-MS/MS of H37Rv and two clinical isolates of Mycobacterium tuberculosis
  description: Clinical isolates were made available from an extensive longitudinal collection of M. tuberculosis isolates circulating in the Western Cape of South Africa. Clinical isolates SAWC3651 and SAWC3517, belonging to the LAM (lineage 4.3) genotype and IS6110 family 14 and 9, respectively, and M. tuberculosis H37Rv were selected for analysis. Proteins were fractionated by SDS-PAGE, using a 4-12% gradient, 1.0 mm NuPage gel (Invitrogen, Carlsbad, CA, USA). Each gel lane was divided into 10 fractions and each fraction was prepared for analysis by mass spectrometry.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Tuberculosis"). Retrieved 2026-08-02.

experimental_models:
- name: Autologous iPSC-derived alveolus-on-chip (iLoC) Mtb infection model
  description: >-
    A single-donor human iPSC-derived lung-on-chip containing alveolar type 1 and
    type 2 epithelial cells, vascular endothelial cells, and iPSC-derived
    macrophages, under air-liquid interface with three-dimensional cyclic
    stretch. Because every cell type derives from one donor, the model is
    autologous and genetically tractable: an ATG14 knockout confined to the
    macrophage compartment can be combined with wild-type epithelium and
    endothelium to isolate a cell-type-specific autophagy requirement, which is
    not achievable in a patient or in a whole-animal knockout.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  cell_types:
  - preferred_term: Pulmonary alveolar type 2 cell
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  - preferred_term: Pulmonary alveolar type 1 cell
    term:
      id: CL:0002062
      label: pulmonary alveolar type 1 cell
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  conditions:
  - Mycobacterium tuberculosis infection
  - ATG14 knockout macrophage compartment
  - static versus breathing (cyclic stretch)
  cell_source: Single-donor human induced pluripotent stem cells (autologous across all compartments)
  culture_system: Microfluidic alveolus-on-chip with air-liquid interface and cyclic mechanical stretch
  publication: PMID:41477823
  modeled_mechanisms:
  - target: Phagocytosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Alveolar macrophages and epithelial cells take up Mtb, reproducing the
      initial uptake step in a human alveolar microenvironment.
    limitations: >-
      The macrophage compartment is iPSC-derived rather than tissue-resident
      alveolar macrophage, and the chip carries no recruited neutrophils or
      lymphocytes, so uptake occurs without the wider cellular context of a
      human alveolus.
    readouts:
    - name: Intracellular Mtb in macrophages and alveolar epithelium
      target: Phagocytosis
      direction: INCREASED
      interpretation: Confirms uptake of bacilli by both compartments after infection.
      evidence:
      - reference: PMID:41477823
        reference_title: Autologous human iPSC-derived alveolus-on-chip reveals early pathological events
          of Mycobacterium tuberculosis infection.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Infection of the iLoC with the human pathogen Mycobacterium tuberculosis (Mtb) showed
          that both macrophages and epithelial cells were infected but not permissive to bacterial replication.
        explanation: Documents uptake into both cell compartments, the readout for this node.
    evidence:
    - reference: PMID:41477823
      reference_title: Autologous human iPSC-derived alveolus-on-chip reveals early pathological events
        of Mycobacterium tuberculosis infection.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Together, we report an autologous, genetically tractable human alveolar model to study lung
        diseases and therapies.
      explanation: Supports treating the chip as an informative human alveolar model for early infection
        events.
  - target: GBP4-Mediated Autophagy-Dependent TB Restriction
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      A macrophage-restricted ATG14 knockout tests the autophagy requirement
      directly. The result refines the usual framing: ATG14 loss raised
      macrophage necrosis without permitting bacterial replication, separating
      autophagy's role in host-cell survival from its role in bacterial
      restriction.
    limitations: >-
      ATG14 is not GBP4, and the chip result speaks to the autophagy machinery
      this node invokes rather than to GBP4 specifically. The perturbation is
      also a complete knockout rather than the partial, regulated variation seen
      in human infection.
    readouts:
    - name: Macrophage necrosis in ATG14-knockout versus wild-type macrophages
      target: GBP4-Mediated Autophagy-Dependent TB Restriction
      direction: INCREASED
      interpretation: >-
        Autophagy deficiency increases infected-macrophage death without
        increasing bacterial burden, indicating the pathway protects the host
        cell rather than only restricting the bacterium here.
      evidence:
      - reference: PMID:41477823
        reference_title: Autologous human iPSC-derived alveolus-on-chip reveals early pathological events
          of Mycobacterium tuberculosis infection.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: A genetically engineered autophagy-deficient iLoC revealed that after Mtb infection, macrophage
          necrosis was higher upon ATG14 deficiency without bacterial replication.
        explanation: The direct readout of the autophagy perturbation in this model.
    evidence:
    - reference: PMID:41477823
      reference_title: Autologous human iPSC-derived alveolus-on-chip reveals early pathological events
        of Mycobacterium tuberculosis infection.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Using a genetically engineered ATG14KO hybrid GE-iLoC, we found that ATG14-deficient macrophages
        are more susceptible to cell death under homeostatic and Mtb-infected conditions.
      explanation: Supports the chip as a system for interrogating autophagy dependence in this node.
  - target: Granuloma Formation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Large macrophage aggregates with a necrotic core arose stochastically and
      supported focal Mtb replication, an early necrotic-aggregate structure
      resembling the initiating step of granuloma formation.
    limitations: >-
      These aggregates are not granulomas. They lack lymphocytic cuffing,
      epithelioid and multinucleate giant-cell differentiation, and fibrotic
      encapsulation, form only stochastically, and arise over days rather than
      the weeks of granuloma maturation in vivo. The chip has no adaptive immune
      compartment, so the T-cell-dependent stages cannot occur at all.
    readouts:
    - name: Macrophage aggregates with necrotic core supporting focal Mtb replication
      target: Granuloma Formation
      direction: INCREASED
      interpretation: >-
        A necrotic-core aggregate is the earliest structural correlate of
        granuloma initiation available in this system.
      evidence:
      - reference: PMID:41477823
        reference_title: Autologous human iPSC-derived alveolus-on-chip reveals early pathological events
          of Mycobacterium tuberculosis infection.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Stochastically, large macrophage clusters containing necrotic macrophages supporting Mtb
          replication were observed.
        explanation: Reports the necrotic macrophage aggregate; PARTIAL because a stochastic aggregate
          is only the initiating step of the granuloma this node describes.
    evidence:
    - reference: PMID:41477823
      reference_title: Autologous human iPSC-derived alveolus-on-chip reveals early pathological events
        of Mycobacterium tuberculosis infection.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Stochastically, large macrophage clusters containing necrotic macrophages supporting Mtb
        replication were observed.
      explanation: Supports limited, early-stage relevance of the chip to granuloma formation.
  - target: Tissue Damage
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Foci of aggregated cell death progressed to severe disruption of both the
      epithelial and endothelial layers, reproducing the barrier destruction that
      underlies tuberculous tissue damage.
    limitations: >-
      Damage is confined to the two cellular layers on the chip; there is no
      matrix remodelling, cavitation, or vascular thrombosis, which are central
      to tissue damage in human pulmonary tuberculosis.
    readouts:
    - name: Epithelial and endothelial barrier integrity
      target: Tissue Damage
      direction: DECREASED
      interpretation: Barrier destruction at foci of cell death is the tissue-damage readout in this model.
      evidence:
      - reference: PMID:41477823
        reference_title: Autologous human iPSC-derived alveolus-on-chip reveals early pathological events
          of Mycobacterium tuberculosis infection.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: However, we observed areas of cell death aggregation and Mtb replication that progressed
          to a severe disruption of both the epithelial and endothelial barrier.
        explanation: Directly reports the barrier destruction this readout measures.
    evidence:
    - reference: PMID:41477823
      reference_title: Autologous human iPSC-derived alveolus-on-chip reveals early pathological events
        of Mycobacterium tuberculosis infection.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: However, we observed areas of cell death aggregation and Mtb replication that progressed
        to a severe disruption of both the epithelial and endothelial barrier.
      explanation: Supports the chip as informative for tuberculous alveolar tissue damage.
  - target: Immune Evasion
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Neither macrophages nor epithelial cells were permissive to Mtb
      replication, in contrast to conventional two-dimensional cultures where
      Mtb replicates within 48 hours and to human disease where progressive
      intracellular replication is the norm. The chip therefore does not
      reproduce sustained evasion of intracellular killing, and replication
      appeared only in rare necrotic foci.
    limitations: >-
      Non-permissiveness may reflect the immaturity of iPSC-derived macrophages,
      the absence of the immunosuppressive signals of an established lesion, or
      the short observation window, rather than a genuine property of the human
      alveolus. Until that is resolved, the model should not be used to score
      evasion phenotypes or to screen compounds whose readout is restriction of
      intracellular replication.
    readouts:
    - name: Intracellular Mtb replication over 48 hours
      target: Immune Evasion
      direction: UNCHANGED
      interpretation: >-
        Absence of replication where 2D culture and human disease both show it is
        a negative result that bounds the model's use.
      evidence:
      - reference: PMID:41477823
        reference_title: Autologous human iPSC-derived alveolus-on-chip reveals early pathological events
          of Mycobacterium tuberculosis infection.
        supports: REFUTE
        evidence_source: IN_VITRO
        snippet: In the iLoC, macrophages and epithelial cells are not permissive for Mtb replication as
          compared to 2D in vitro cultures.
        explanation: Explicit statement that the model does not support the intracellular replication
          that immune evasion in human tuberculosis entails.
    evidence:
    - reference: PMID:41477823
      reference_title: Autologous human iPSC-derived alveolus-on-chip reveals early pathological events
        of Mycobacterium tuberculosis infection.
      supports: REFUTE
      evidence_source: IN_VITRO
      snippet: In the iLoC, macrophages and epithelial cells are not permissive for Mtb replication as
        compared to 2D in vitro cultures.
      explanation: Substantiates the negative claim that this model fails to recapitulate sustained
        intracellular persistence.

📚

References & Deep Research

Deep Research

2

Disorder ▸

Disorder

Name: Tuberculosis
Category: Infectious Disease
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 109

Key Pathophysiology Nodes

Phagocytosis
Granuloma Formation
Neutrophil Activation and NETosis
Tissue Damage
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1016/j.celrep.2024.115072
DOI:10.1101/2025.07.15.664002
DOI:10.1128/spectrum.01188-24
DOI:10.3389/fimmu.2023.1305325
DOI:10.3389/fimmu.2024.1402024
DOI:10.3390/ijms25158196

Falcon ▸

Pathophysiology Description

Edison Scientific Literature 19 citations 2025-12-15T10:10:08.032076

Pathophysiology Description Mycobacterium tuberculosis (Mtb) subverts innate immune defenses through specialized secretion systems, metabolic reprogramming of host phagocytes, and induction of maladaptive inflammatory programs. Type VII secretion, especially ESX-1, promotes phagosomal membrane damage and cytosolic access, which triggers cytosolic DNA sensing through cGAS–STING–TBK1 and induction of type I interferon (IFN) programs; ESX effectors can concomitantly inhibit autophagy and impair phagosome maturation, facilitating intracellular survival (jiang2024mycobacteriumtuberculosisvii pages 1-2). Metabolic rewiring of macrophage cholesterol handling fuels foamy macrophage formation and creates nutrient-rich, permissive niches (chen2024theimpactof pages 1-2). In the lung, spatial single-cell and spatial-transcriptomic profiling indicates distinct microenvironments: alveolar regions harbor TREM2+ foamy macrophages enriched for lipid handling genes and Mtb antigens, whereas granuloma cores exhibit interferon-driven antimicrobial signatures (teles2025spatialprofilingreveals pages 5-8, teles2025spatialprofilingreveals pages 8-11). Neutrophils contribute importantly to immunopathology; type I IFN–linked neutrophil programs and neutrophil extracellular traps (NETs) correlate with tissue damage and relapse risk, positioning NET-associated pathways as potential host-directed therapy (HDT) targets (saqib2025pathogenicrolefor pages 26-27). Inflammasome pathways (e.g., NLRP3/AIM2→caspase-1→IL‑1β) have context-dependent roles in early control versus pathology and are actionable in HDT concepts (cebani2024canweexploit pages 1-2).

Key Concepts and Definitions with Current Understanding - Type VII secretion (ESX-1): A specialized secretion system that exports virulence substrates (e.g., EsxA/ESAT‑6 and EsxB/CFP‑10) to permeabilize the phagosomal membrane, enabling cytosolic access and engagement of host DNA sensors (jiang2024mycobacteriumtuberculosisvii pages 1-2). - Cytosolic DNA sensing (cGAS–STING–TBK1): Host pathway that detects bacterial DNA in the cytosol and induces type I IFN responses; in TB, activation can both promote antimicrobial programs and drive detrimental inflammation depending on timing and magnitude (jiang2024mycobacteriumtuberculosisvii pages 1-2). - Foamy macrophages: Lipid droplet–rich macrophages formed through increased cholesterol uptake/synthesis and impaired efflux, supporting Mtb persistence and TB progression (chen2024theimpactof pages 1-2). In human TB lungs, a TREM2+ foamy macrophage program is spatially concentrated in alveoli (teles2025spatialprofilingreveals pages 5-8, teles2025spatialprofilingreveals pages 8-11). - NETosis/NETs: Neutrophil extracellular traps contribute to TB tissue pathology (caseating granulomas, vascular occlusion) and may be driven by IFN-linked programs; restraining NET formation can improve outcomes in relevant models (saqib2025pathogenicrolefor pages 26-27). - Inflammasomes: Canonical (e.g., NLRP3, AIM2) and non-canonical (caspase‑4/5/11) complexes mature IL‑1β/IL‑18 and drive pyroptosis; balanced modulation is a candidate HDT strategy in TB (cebani2024canweexploit pages 1-2).

Recent Developments and Latest Research (2023–2024 priority) - ESX effector Rv2347c/EsxP: “Rv2347c … inhibits the expression of the early marker RAB5 of phagosomes … triggers the host’s cytoplasmic sensing pathway STING/TBK1, inhibiting autophagy and upregulating IFNβ transcription” (Microbiology Spectrum, Nov 2024; DOI: 10.1128/spectrum.01188-24) (jiang2024mycobacteriumtuberculosisvii pages 1-2). - Macrophage cholesterol metabolism: Mtb increases LDL uptake and de novo cholesterol synthesis, suppresses cholesterol ester hydrolysis and ABC-transporter–mediated efflux, driving lipid droplet accumulation and foam cell formation that facilitates persistence and granuloma/cavitation (Frontiers in Immunology, May 2024; DOI: 10.3389/fimmu.2024.1402024) (chen2024theimpactof pages 1-2). - Spatial single-cell mapping in human TB: Alveoli/pneumonia regions contain TREM2+ foamy macrophages enriched for lipid metabolism (APOE, LIPA, NPC2, PLIN2), while granuloma cores show IFN-activated macrophages and higher expression of antimicrobial genes; TREM2 colocalizes with lipid droplets and Mtb antigens (bioRxiv, Aug 2025; DOI: 10.1101/2025.07.15.664002) (teles2025spatialprofilingreveals pages 5-8, teles2025spatialprofilingreveals pages 8-11). - Neutrophil pathogenic programs: Type I IFN–linked neutrophil responses drive lung inflammation, NETosis, and pathology; specific neutrophil subsets (e.g., CD101‑negative) and NET-associated mechanisms are implicated as targets (Cell Reports, Jan 2025; DOI: 10.1016/j.celrep.2024.115072) (saqib2025pathogenicrolefor pages 26-27). - Inflammasome HDT concepts: Reviews detail priming (TLRs→NF‑κB), activation (NLRP3/AIM2), caspase‑1/11/4/5, gasdermin D, and IL‑1 family maturation as targets for precision modulation in TB (IJMS, Jul 2024; DOI: 10.3390/ijms25158196) (cebani2024canweexploit pages 1-2).

Current Applications and Real‑World Implementations - Pathway-informed HDTs: Reviews emphasize adjunctive HDTs to enhance autophagy, temper excessive inflammasome activity, or reprogram macrophage lipid metabolism alongside antibiotics, including repurposed drugs and small molecules (Frontiers in Immunology, Jan 2024; DOI: 10.3389/fimmu.2023.1305325) (zhao2024hostdirectedtherapyagainst pages 14-14). Translational implications also extend to NET inhibition strategies where excessive NETosis drives tissue injury (saqib2025pathogenicrolefor pages 26-27). - Spatially guided targets: Spatial profiling highlights distinct compartments (alveoli versus granuloma core) and cell states (TREM2+ foamy versus IFN-activated macrophages), guiding localized or state-specific interventions (teles2025spatialprofilingreveals pages 5-8, teles2025spatialprofilingreveals pages 8-11).

Expert Opinions and Analysis from Authoritative Sources - ESX-1 as central virulence hub: The 2024 Microbiology Spectrum study and related literature converge on ESX-1 as a driver of phagosomal rupture and downstream type I IFN induction, with specific effectors (e.g., EsxP) also inhibiting autophagy—an actionable axis for antivirulence or HDT strategies (jiang2024mycobacteriumtuberculosisvii pages 1-2). - Lipid metabolism as a therapeutic node: The 2024 Frontiers in Immunology review argues that reducing host cholesterol availability or restoring efflux can limit Mtb invasion and enhance antibiotic efficacy—offering a rational HDT direction (chen2024theimpactof pages 1-2). - Compartmentalized pathophysiology: Spatial single-cell work reveals alveoli enriched in lipid‑handling macrophages harboring Mtb antigens, versus granuloma cores with IFN‑driven antimicrobial programs—supporting tailored interventions by lesion context (teles2025spatialprofilingreveals pages 5-8, teles2025spatialprofilingreveals pages 8-11). - NETs as double-edged swords: Neutrophil/NET programs are repeatedly implicated in advanced disease; strategies that limit NETosis (e.g., PAD4 inhibition) without broadly suppressing host defense merit investigation (saqib2025pathogenicrolefor pages 26-27). - Inflammasome balance: Reviews stress that both insufficient and excessive inflammasome activity are harmful, advocating precision modulation rather than wholesale suppression (cebani2024canweexploit pages 1-2).

Relevant Statistics and Data from Recent Studies - Spatial single-cell atlas (human pulmonary TB): 45,023 single cells profiled (avg. ~1,017 genes/cell), 27 cell types (10 myeloid, 7 lymphocyte); TREM2+ foamy macrophages localized to alveoli; granuloma cores with higher antimicrobial gene expression (e.g., 15 genes significantly higher vs alveoli, adjusted p = 3.72×10⁻⁷) (bioRxiv, Aug 2025; DOI: 10.1101/2025.07.15.664002) (teles2025spatialprofilingreveals pages 5-8). - TREM2 induction by mycobacterial lipids: Mycolic acids and PDIM induced ~50–55% TREM2+ macrophages in vitro; live Mtb induced ~30% TREM2+ cells; TREM2–DAP12 reporter correlated with activation (r=0.93, p=0.007) (bioRxiv, Aug 2025; DOI: 10.1101/2025.07.15.664002) (teles2025spatialprofilingreveals pages 8-11).

Core Pathophysiology - Primary mechanisms: ESX-1–mediated phagosome damage and cytosolic translocation; cGAS–STING–TBK1–IRF3 activation and type I IFN responses; autophagy inhibition by ESX effectors; host lipid metabolic reprogramming→foamy macrophages; neutrophil activation and NETosis; compartmentalized lesion biology (jiang2024mycobacteriumtuberculosisvii pages 1-2, chen2024theimpactof pages 1-2, teles2025spatialprofilingreveals pages 5-8, saqib2025pathogenicrolefor pages 26-27). - Dysregulated pathways: Type I IFN signaling, autophagy, cholesterol uptake/efflux and ester metabolism, inflammasome activation (jiang2024mycobacteriumtuberculosisvii pages 1-2, chen2024theimpactof pages 1-2, cebani2024canweexploit pages 1-2). - Affected cellular processes: Phagosome maturation/lysosome fusion, xenophagy/autophagy flux, lipid droplet biogenesis, NET formation, IFN-stimulated gene programs (jiang2024mycobacteriumtuberculosisvii pages 1-2, chen2024theimpactof pages 1-2, saqib2025pathogenicrolefor pages 26-27).

Key Molecular Players - Genes/Proteins: EsxA/EsxB (ESX-1), Rv2347c/EsxP, cGAS, STING, TBK1, IRF3, IFN‑β, TREM2, APOE, NPC2, PLIN2, LIPA, ABC transporters (ABCA1/ABCG1 class), IL‑1β (jiang2024mycobacteriumtuberculosisvii pages 1-2, chen2024theimpactof pages 1-2, teles2025spatialprofilingreveals pages 5-8, cebani2024canweexploit pages 1-2). - Chemical entities: Cholesterol (ChEBI:28694); interferon‑β; NET-modulatory agents (e.g., PAD4 inhibitors) as conceptual HDTs (chen2024theimpactof pages 1-2, saqib2025pathogenicrolefor pages 26-27). - Cell types: Macrophages (alveolar, TREM2+ foamy, IFN-activated), neutrophils, Th17 cells, dendritic cells (teles2025spatialprofilingreveals pages 5-8, saqib2025pathogenicrolefor pages 26-27). - Anatomical locations: Alveoli/pneumonia regions versus granuloma cores/mantles (teles2025spatialprofilingreveals pages 5-8).

Biological Processes (GO) for Annotation - Type I interferon signaling (GO:0034138): cGAS–STING–TBK1–IRF3–IFNβ axis following ESX-1–mediated cytosolic access (jiang2024mycobacteriumtuberculosisvii pages 1-2). - Autophagy/xenophagy (GO:0006914): Targeted and inhibited by ESX effectors; HDT target (jiang2024mycobacteriumtuberculosisvii pages 1-2). - Lipid metabolic process (GO:0006629): Cholesterol uptake/synthesis, esterification and impaired efflux leading to foamy macrophages (chen2024theimpactof pages 1-2). - Cholesterol transport (GO:0030301): ABC transporter–mediated efflux is suppressed during infection (chen2024theimpactof pages 1-2). - Neutrophil degranulation/NET formation (GO:0043312): Contributes to tissue injury and relapse risk (saqib2025pathogenicrolefor pages 26-27). - Inflammasome complex assembly and IL‑1β maturation: Context-dependent protective/pathologic roles; HDT node (cebani2024canweexploit pages 1-2).

Cellular Components - Phagosome and phagolysosome membranes; cytosol (site of cGAS–STING sensing after ESX-mediated rupture) (jiang2024mycobacteriumtuberculosisvii pages 1-2). - Lipid droplets (PLIN2+) and lysosomes (NPC2/LIPA) in foamy macrophages (teles2025spatialprofilingreveals pages 5-8, chen2024theimpactof pages 1-2). - Extracellular region (NETs); inflammasome complexes (cytosolic) (saqib2025pathogenicrolefor pages 26-27, cebani2024canweexploit pages 1-2).

Disease Progression (sequence of events) - Inhalation and alveolar deposition → uptake by alveolar macrophages → ESX-1–mediated phagosome damage and cytosolic access → cGAS–STING–TBK1–IRF3 activation and type I IFN programs; autophagy inhibition by ESX effectors (e.g., EsxP) → metabolic rewiring of macrophages to lipid-laden, TREM2+ foamy states in alveoli → lesion heterogeneity with granuloma cores enriched for IFN‑activated antimicrobial signatures and neutrophil influx/NETs in progressive disease → cavitation and dissemination in advanced disease (jiang2024mycobacteriumtuberculosisvii pages 1-2, chen2024theimpactof pages 1-2, teles2025spatialprofilingreveals pages 5-8, saqib2025pathogenicrolefor pages 26-27).

Phenotypic Manifestations (mechanism–phenotype links) - Caseating necrosis and tissue destruction: Associated with neutrophil-driven inflammation and NETosis; vascular occlusions with neutrophil aggregates reported in TB (mechanistic framework; NETs) (saqib2025pathogenicrolefor pages 26-27). - Alveolar pneumonia with macrophage lipid accumulation: TREM2+ foamy macrophages colocalize with Mtb antigens and lipid droplets in alveoli (teles2025spatialprofilingreveals pages 5-8, teles2025spatialprofilingreveals pages 8-11). - Granuloma core IFN bias: IFN-driven antimicrobial gene expression and IFN-activated macrophage states correspond to granuloma cores (teles2025spatialprofilingreveals pages 5-8).

Evidence Items with URLs and Publication Dates - Jiang et al., 2024 (Microbiology Spectrum, Nov 2024): “Rv2347c … blocks the maturation of phagosomes … activates the STING/TBK1 signaling pathway to inhibit cell autophagy” (DOI: 10.1128/spectrum.01188-24; https://doi.org/10.1128/spectrum.01188-24) (jiang2024mycobacteriumtuberculosisvii pages 1-2). - Chen et al., 2024 (Frontiers in Immunology, May 30, 2024): “Mtb infection increases the uptake of LDL and cholesterol … suppresses ABC transporters … promoting the formation of lipid droplets and foam cells” (DOI: 10.3389/fimmu.2024.1402024; https://doi.org/10.3389/fimmu.2024.1402024) (chen2024theimpactof pages 1-2). - Teles et al., 2025 preprint (bioRxiv, Aug 2025): Spatial profiling of human TB lungs identifies TREM2+ foamy macrophages in alveoli and IFN-activated programs in granuloma cores; TREM2 colocalizes with PLIN2 and Mtb antigens; mycolic acids/PDIM induce ~50–55% TREM2+ macrophages (DOI: 10.1101/2025.07.15.664002; https://doi.org/10.1101/2025.07.15.664002) (teles2025spatialprofilingreveals pages 5-8, teles2025spatialprofilingreveals pages 8-11). - Saqib et al., 2025 (Cell Reports, Jan 2025): Type I IFN–mediated neutrophil programs drive immunopathology and NETosis; NETs implicated in TB tissue damage and as therapeutic targets (DOI: 10.1016/j.celrep.2024.115072; https://doi.org/10.1016/j.celrep.2024.115072) (saqib2025pathogenicrolefor pages 26-27). - Cebani & Mvubu, 2024 (International Journal of Molecular Sciences, Jul 2024): Inflammasome pathways (NLRP3/AIM2→caspase‑1→IL‑1β; non‑canonical caspase‑4/5/11) as HDT targets in TB (DOI: 10.3390/ijms25158196; https://doi.org/10.3390/ijms25158196) (cebani2024canweexploit pages 1-2). - Zhao et al., 2024 (Frontiers in Immunology, Jan 2024): Review of HDT strategies for TB and TB–diabetes comorbidity, including autophagy promotion and immunomodulation (DOI: 10.3389/fimmu.2023.1305325; https://doi.org/10.3389/fimmu.2023.1305325) (zhao2024hostdirectedtherapyagainst pages 14-14).

Structured, Ontology-Linked Annotations | Category | Entity (identifier) | Role in TB | Key Process/Pathway (GO) | Cellular Component (GO/CC) | Cell Type (CL) | Anatomical Site (UBERON) | Chemical/Drug (ChEBI) | Evidence | |---|---|---|---|---|---|---|---|---| | Secretion system | ESX-1 (Type VII secretion system) | Mediates phagosomal membrane permeabilization and secretion of ESX substrates that enable cytosolic access and immune modulation | secretion / phagosomal membrane permeabilization (ESX-1 function) | bacterial secretion apparatus / phagosome membrane | infected macrophage (CL:0000235) | alveolus of lung (UBERON:0008952) | — | Microbiology Spectrum doi:10.1128/spectrum.01188-24; Nov 2024 (jiang2024mycobacteriumtuberculosisvii pages 1-2) | | Effector proteins | EsxA / EsxB (ESAT-6 / CFP-10) | Pore-forming effectors that contribute to phagosomal rupture and downstream host sensing | (ESX-1 substrate secretion) | phagosomal membrane / pore complex | macrophage (CL:0000235) | phagosome / cytosol (lung) | — | Microbiology Spectrum doi:10.1128/spectrum.01188-24; Nov 2024 (jiang2024mycobacteriumtuberculosisvii pages 1-2) | | Effector protein | Rv2347c / EsxP (Rv2347c) | Blocks phagosome maturation, promotes phagosome escape → activates STING/TBK1 → ↑IFN-β and inhibits autophagy | GO:0034138 type I interferon signaling pathway; GO:0006914 autophagy (inhibition) | phagosome / cytosol; STING-associated membranes | macrophage (CL:0000235) | alveolus of lung (UBERON:0008952) | — | Microbiology Spectrum doi:10.1128/spectrum.01188-24; Nov 2024 (jiang2024mycobacteriumtuberculosisvii pages 1-2) | | Cytosolic DNA sensor axis | cGAS–STING–TBK1–IRF3 → IFN-β | Cytosolic DNA sensing of escaped Mtb triggers type I IFN responses that can be host-protective or pathologic depending on timing/amount | GO:0034138 type I interferon signaling pathway | cytosol; ER-Golgi/ STING localization | macrophage (CL:0000235), dendritic cell | lung parenchyma / granuloma core | interferon-β (ChEBI:interferon-β) | Microbiology Spectrum doi:10.1128/spectrum.01188-24; Nov 2024; Cell Reports summary (jiang2024mycobacteriumtuberculosisvii pages 1-2, saqib2025pathogenicrolefor pages 26-27) | | Autophagy | Host autophagy (xenophagy) | Autophagy is inhibited by ESX effectors (promotes Mtb survival); restoration is an HDT target | GO:0006914 autophagy | autophagosome / lysosome (GO:0005764) | macrophage (CL:0000235) | intracellular compartment (lung) | mTOR inhibitors / autophagy inducers (e.g., rapamycin) | Microbiology Spectrum doi:10.1128/spectrum.01188-24; Nov 2024 (jiang2024mycobacteriumtuberculosisvii pages 1-2) | | Lipid uptake receptor | CD36 (CD36) | Scavenger receptor mediating uptake of lipids/cholesterol → supports foamy macrophage phenotype that favours Mtb persistence | GO:0006629 lipid metabolic process | plasma membrane; endocytic vesicles | macrophage (CL:0000235) | alveolus of lung (UBERON:0008952) | cholesterol (ChEBI:28694) | Frontiers in Immunology doi:10.3389/fimmu.2024.1402024; May 2024 (chen2024theimpactof pages 1-2) | | Lipid handling protein | APOE (apolipoprotein E) | Mediates lipid trafficking; part of TREM2+/foamy macrophage signature and linked to permissive intracellular niche | GO:0006629 lipid metabolic process | lipid particles / extracellular region | macrophage (CL:0000235) | alveolar space (UBERON:0008952) | cholesterol / apolipoproteins (ChEBI:28694) | Spatial/transcriptomic data (TREM2+ program) doi:10.1101/2025.07.15.664002; Aug 2025 (teles2025spatialprofilingreveals pages 5-8) | | Intracellular lipid transporter | NPC2 (NPC2) | Lysosomal cholesterol handling; part of foamy macrophage / lipid-droplet program associated with permissive Mtb niches | GO:0030301 cholesterol transport | lysosome / lipid droplet | macrophage (CL:0000235) | alveolus / macrophage lipid droplet | cholesterol (ChEBI:28694) | Spatial/transcriptomic data doi:10.1101/2025.07.15.664002; Aug 2025 (teles2025spatialprofilingreveals pages 5-8) | | Lipid droplet marker | PLIN2 (perilipin-2) | Marks lipid droplets / foamy macrophages that harbor Mtb antigens; indicates altered host lipid storage | GO:0006629 lipid metabolic process | lipid droplet (GO:0005811) | macrophage (CL:0000235) | alveoli / pneumonia regions (UBERON:0008952) | neutral lipids (ChEBI:5891) | Spatial/transcriptomic data doi:10.1101/2025.07.15.664002; Aug 2025 (teles2025spatialprofilingreveals pages 5-8) | | Lipase / lipid catabolism | LIPA (lysosomal acid lipase) | Lysosomal hydrolysis of cholesteryl esters / triglycerides; dysregulated in infected macrophages | GO:0006631 fatty acid metabolic process | lysosome | macrophage (CL:0000235) | alveolus / phagolysosome | cholesterol esters (ChEBI:??) | Frontiers in Immunology doi:10.3389/fimmu.2024.1402024; May 2024 (chen2024theimpactof pages 1-2) | | Cholesterol efflux | ABC transporters (e.g., ABCA1/ABCG1) | Reduced expression during Mtb infection → impaired cholesterol efflux → foam cell formation | GO:0030301 cholesterol transport | plasma membrane / lipid raft | macrophage (CL:0000235) | alveolus / lung | cholesterol (ChEBI:28694) | Frontiers in Immunology doi:10.3389/fimmu.2024.1402024; May 2024 (chen2024theimpactof pages 1-2) | | Macrophage subset | TREM2+ foamy macrophages | Lipid-laden, permissive macrophage population concentrated in alveoli; colocalize with Mtb antigens and lipid droplets | GO:0006629 lipid metabolic process | lipid droplets; phagolysosome | macrophage (CL:0000235; TREM2+ subset) | alveolus of lung (UBERON:0008952) | — | Spatial/transcriptomic & proteomics doi:10.1101/2025.07.15.664002; Aug 2025 (teles2025spatialprofilingreveals pages 5-8) | | Neutrophil effector structures | NETs (MPO, neutrophil elastase; PAD4-dependent) | NETosis characterizes caseating granulomas; contributes to tissue damage, immunothrombosis and relapse risk | GO:0043312 neutrophil degranulation / NET formation | extracellular traps (extracellular region) | neutrophil (CL:0000775) | granuloma core / pulmonary vessels | PAD4 inhibitors (e.g., Cl-amidine) | Cell Reports / review summaries doi:10.1016/j.celrep.2024.115072; Jan 2025 (saqib2025pathogenicrolefor pages 26-27) | | Inflammasome pathway | NLRP3 / AIM2 → caspase-1 → IL-1β | Canonical inflammasomes mature IL-1β/IL-18 and drive pyroptosis; dual role (control vs tissue damage); candidate HDT targets | (inflammasome activation; IL-1β maturation) | inflammasome complex (cytosol) | macrophage / DC (CL:0000235; CL:0001056) | granuloma / lung | IL-1β (ChEBI:17052) | Int J Mol Sci doi:10.3390/ijms25158196; Jul 2024 (cebani2024canweexploit pages 1-2) | | Spatial compartments | Alveoli (pneumonia) vs granuloma core (lesion) | Distinct programs: alveoli enriched for lipid metabolism/foamy macrophages; granuloma core enriched for IFN-driven antimicrobial programs and SPP1+/IFN-activated macrophages | alveoli: lipid metabolism (GO:0006629); core: type I/II IFN & antimicrobial responses (GO:0034138) | alveolar lumen vs granuloma core | alveolar macrophage (CL:0000235); IFN-activated macrophage | alveolus of lung (UBERON:0008952); granulomatous lesion (region) | — | Spatial single-cell & ROI profiling doi:10.1101/2025.07.15.664002; Aug 2025 (teles2025spatialprofilingreveals pages 5-8) | | Host-directed therapy (HDT) targets | HDT (autophagy inducers, lipid modulators, inflammasome modulators) | Therapeutic strategies to restore autophagy, limit pathological inflammation, or reprogram macrophage lipid handling | autophagy promotion; inflammasome modulation; metabolic reprogramming | various (autophagosome, inflammasome) | macrophage, neutrophil, DC | lung / systemic | candidate drugs cited in reviews (repurposed agents) | Frontiers in Immunology (HDT review) doi:10.3389/fimmu.2023.1305325; Jan 2024 (zhao2024hostdirectedtherapyagainst pages 14-14) |

Table: Concise ontology-ready annotations linking key TB mechanisms, genes/proteins, cell types, compartments, and candidate chemicals with source DOIs and context IDs; useful for knowledge‑base ingestion and evidence-traced curation.

Abbreviations and Ontologies - HGNC: TREM2, APOE, NPC2, PLIN2, LIPA, CD36, TBK1, IRF3, IL1B. - GO: GO:0034138 (type I IFN signaling); GO:0006914 (autophagy); GO:0006629 (lipid metabolism); GO:0030301 (cholesterol transport); GO:0043312 (neutrophil degranulation/NET formation). - CL: CL:0000235 (macrophage); CL:0000775 (neutrophil). - UBERON: UBERON:0008952 (alveolus of lung). - CHEBI: CHEBI:28694 (cholesterol).

Limitations and Open Questions - Although type I IFN signatures and NETs are implicated in pathogenesis, the precise windows where IFN or NET modulation improves clinical outcomes remain to be defined in humans (saqib2025pathogenicrolefor pages 26-27). - Spatial single-cell findings are compelling but include preprint data; further peer-reviewed validation and integration with clinical phenotypes are needed (teles2025spatialprofilingreveals pages 5-8, teles2025spatialprofilingreveals pages 8-11).

Overall, contemporary evidence supports a model in which ESX-1–driven cytosolic access and cGAS–STING activation, macrophage lipid reprogramming to TREM2+ foamy states, and type I IFN–linked neutrophil/NET programs collectively drive TB progression, while inflammasome and autophagy pathways offer promising HDT entry points (jiang2024mycobacteriumtuberculosisvii pages 1-2, chen2024theimpactof pages 1-2, teles2025spatialprofilingreveals pages 5-8, saqib2025pathogenicrolefor pages 26-27, cebani2024canweexploit pages 1-2, zhao2024hostdirectedtherapyagainst pages 14-14).

References

(jiang2024mycobacteriumtuberculosisvii pages 1-2): Zhiyong Jiang, Junfeng Zhen, Yuerigu Abulikena, Chaoyun Gao, Lingxi Huang, Tingting Huang, and Jianping Xie. mycobacterium tuberculosis vii secretion system effector molecule rv2347c blocks the maturation of phagosomes and activates the sting/tbk1 signaling pathway to inhibit cell autophagy. Microbiology Spectrum, Nov 2024. URL: https://doi.org/10.1128/spectrum.01188-24, doi:10.1128/spectrum.01188-24. This article has 8 citations and is from a domain leading peer-reviewed journal.
(chen2024theimpactof pages 1-2): Zhanpeng Chen, Xingxing Kong, Quan Ma, Jinyun Chen, Yuqin Zeng, Huazhen Liu, Xiaomin Wang, and Shuihua Lu. The impact of mycobacterium tuberculosis on the macrophage cholesterol metabolism pathway. Frontiers in Immunology, May 2024. URL: https://doi.org/10.3389/fimmu.2024.1402024, doi:10.3389/fimmu.2024.1402024. This article has 19 citations and is from a peer-reviewed journal.
(teles2025spatialprofilingreveals pages 5-8): Rosane M. B. Teles, Chaouki Benabdessalem, Jonathan Perrie, Cenfu Wei, Julie West, Bruno J. de Andrade Silva, Priscila R. Andrade, Lilah A. Mansky, Prajan Divakar, Linda Fischbacher, Karen Lam, Feiyang Ma, Kimia Rategh, Aparna Pillai, Samuel M. French, Emna Romdhane, Mohamed-Ridha Barbouche, Eynav Klechevsky, Marco Colonna, Adrie J. C. Steyn, Steven J. Bensinger, Daniel L. Barber, Soumaya Rammeh, Parambir S. Dulai, Bryan D. Bryson, Matteo Pellegrini, John T. Belisle, Barry R. Bloom, and Robert L. Modlin. Spatial profiling reveals trem2+ macrophages as central to mycobacterium tuberculosis pathogenesis in human pulmonary tuberculosis. bioRxiv : the preprint server for biology, Aug 2025. URL: https://doi.org/10.1101/2025.07.15.664002, doi:10.1101/2025.07.15.664002. This article has 0 citations.
(teles2025spatialprofilingreveals pages 8-11): Rosane M. B. Teles, Chaouki Benabdessalem, Jonathan Perrie, Cenfu Wei, Julie West, Bruno J. de Andrade Silva, Priscila R. Andrade, Lilah A. Mansky, Prajan Divakar, Linda Fischbacher, Karen Lam, Feiyang Ma, Kimia Rategh, Aparna Pillai, Samuel M. French, Emna Romdhane, Mohamed-Ridha Barbouche, Eynav Klechevsky, Marco Colonna, Adrie J. C. Steyn, Steven J. Bensinger, Daniel L. Barber, Soumaya Rammeh, Parambir S. Dulai, Bryan D. Bryson, Matteo Pellegrini, John T. Belisle, Barry R. Bloom, and Robert L. Modlin. Spatial profiling reveals trem2+ macrophages as central to mycobacterium tuberculosis pathogenesis in human pulmonary tuberculosis. bioRxiv : the preprint server for biology, Aug 2025. URL: https://doi.org/10.1101/2025.07.15.664002, doi:10.1101/2025.07.15.664002. This article has 0 citations.
(saqib2025pathogenicrolefor pages 26-27): Mohd Saqib, Shreya Das, Tanvir N. Nafiz, Elizabeth McDonough, Poornima Sankar, Lokesh K. Mishra, Ximeng Zhang, Yi Cai, Selvakumar Subbian, and Bibhuti B. Mishra. Pathogenic role for cd101-negative neutrophils in the type i interferon-mediated immunopathogenesis of tuberculosis. Cell Reports, 44:115072, Jan 2025. URL: https://doi.org/10.1016/j.celrep.2024.115072, doi:10.1016/j.celrep.2024.115072. This article has 16 citations and is from a highest quality peer-reviewed journal.
(cebani2024canweexploit pages 1-2): Lilitha Cebani and Nontobeko E. Mvubu. Can we exploit inflammasomes for host-directed therapy in the fight against mycobacterium tuberculosis infection? International Journal of Molecular Sciences, 25:8196, Jul 2024. URL: https://doi.org/10.3390/ijms25158196, doi:10.3390/ijms25158196. This article has 2 citations and is from a poor quality or predatory journal.
(zhao2024hostdirectedtherapyagainst pages 14-14): Li Zhao, Ke Fan, Xuezhi Sun, Wei Li, Fenfen Qin, Liwen Shi, Feng Gao, and Chunlan Zheng. Host-directed therapy against mycobacterium tuberculosis infections with diabetes mellitus. Frontiers in Immunology, Jan 2024. URL: https://doi.org/10.3389/fimmu.2023.1305325, doi:10.3389/fimmu.2023.1305325. This article has 13 citations and is from a peer-reviewed journal.

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