◆

Subtypes

3

Seasonal Influenza

Annual epidemics caused by circulating influenza A and B strains undergoing antigenic drift.

Show evidence (1 reference)

PMID:29955068 SUPPORT Human Clinical

"Influenza vaccines are formulated every year to match the circulating strains, as they evolve antigenically owing to antigenic drift."

Describes the annual reformulation needed due to antigenic drift driving seasonal epidemics.

Pandemic Influenza

Global outbreaks caused by novel influenza A subtypes to which the population has little or no pre-existing immunity, arising from antigenic shift.

Show evidence (1 reference)

PMID:29955068 SUPPORT Human Clinical

"The most severe influenza pandemic, in 1918, resulted in >40 million deaths worldwide."

Documents pandemic influenza and its catastrophic potential.

Avian Influenza

Influenza caused by avian-origin influenza A viruses (e.g., H5N1, H7N9) that can occasionally infect humans with high case fatality rates.

C

Comorbidities

Influenza <-> Alzheimer Disease

Influenza <-> Myocardial Infarction

⚙

Pathophysiology

6

Respiratory Epithelial Infection and Cytopathic Effect

Influenza viruses bind to sialic acid residues on respiratory epithelial cells via hemagglutinin, followed by endocytosis and viral replication in the nucleus. Viral neuraminidase facilitates release of new virions. This causes direct cytopathic damage to airway epithelium, leading to desquamation, impaired mucociliary clearance, and susceptibility to secondary bacterial infection.

respiratory epithelial cell CL:0002632 alveolar macrophage CL:0000583

viral genome replication GO:0019079 defense response to virus GO:0051607

lung UBERON:0002048 respiratory system UBERON:0001004

Experimental models

Immune-competent microvascularized lung-on-a-chip (IC-LOC) severe H1N1 model ORGAN ON CHIP H1N1 infection of the airway compartment produced epithelial cell damage alongside viral replication, reproducing the cytopathic effect of severe influenza on human airway epithelium.

Show evidence (1 reference)

DOI:10.3390/pathogens13070561 SUPPORT Human Clinical

"Influenza virus possesses an RNA genome of single-stranded, negative-sensed, and segmented configuration. Influenza virus causes an acute respiratory disease, commonly known as the "flu" in humans. In some individuals, flu can lead to pneumonia and acute respiratory distress syndrome."

Describes influenza as an acute respiratory disease caused by viral infection of the respiratory tract.

Toll-like Receptor Signaling and Innate Immune Activation

Innate immune sensing of influenza occurs through endosomal TLR3, TLR7, and TLR8. TLR7/8 signal via MYD88 to activate IRF5/IRF7 and NF-kappaB, while TLR3 signals via TRIF to activate IRF3 via TBK1/IKK-epsilon. This dual signaling induces type I and III interferons, pro-inflammatory cytokines, and chemokines. The TLR response is a double-edged sword: necessary for viral control but capable of driving immunopathology when hyperactivated.

dendritic cell CL:0000451 macrophage CL:0000235 neutrophil CL:0000775

toll-like receptor signaling pathway GO:0002224 response to type I interferon GO:0034340

Show evidence (2 references)

DOI:10.3390/ijms25115909 SUPPORT In Vitro

"Because TLRs may act as a double-edged sword, a balanced TLR response is critical for the overall benefit of the host."

Confirms the dual role of TLR signaling in both antiviral defense and immunopathology during influenza.

DOI:10.3390/pathogens13070561 SUPPORT In Vitro

"Host cells sense IAV infection through multiple receptors and mechanisms, which culminate in the induction of a concerted innate antiviral response and the creation of an antiviral state, which inhibits and clears the infection from host cells."

Describes innate antiviral sensing mechanisms including TLR pathways.

Inflammasome Activation and Cytokine Storm

IAV infection activates NLRP3 and AIM2 inflammasomes. AIM2, canonically a cytosolic dsDNA sensor, is activated by host mitochondrial DNA released after IAV-induced mitochondrial damage. Inflammasome activation leads to caspase-1-mediated processing of IL-1-beta and IL-18, and gasdermin D-mediated pyroptosis. Excessive inflammasome activation contributes to the cytokine storm associated with severe influenza.

macrophage CL:0000235

pyroptotic inflammatory response GO:0070269

Experimental models

Immune-competent microvascularized lung-on-a-chip (IC-LOC) severe H1N1 model ORGAN ON CHIP Severe H1N1 infection produced airway and interstitial cytokine profiles matching those measured in bronchoalveolar lavage fluid from patients with severe influenza. Selective inhibition then established directionality: blocking IL-1beta abolished the storm, whereas blocking TNF-alpha worsened it, identifying TNF-alpha as a regulator rather than a driver.

Show evidence (2 references)

DOI:10.3390/v16101535 SUPPORT Model Organism

"Paradoxically, AIM2 deficiency has been linked to both enhanced and reduced vulnerability to IAV infection."

Describes the complex role of AIM2 inflammasome in influenza pathogenesis.

DOI:10.3390/v16101535 SUPPORT Model Organism

"While a strong response is necessary for early viral control, overactivation of inflammasomes can precipitate harmful hyperinflammatory responses, a defining characteristic observed during severe influenza infections."

Confirms that inflammasome overactivation drives hyperinflammation in severe influenza.

PANoptosis and Inflammatory Cell Death

Influenza A virus triggers multiple regulated cell death pathways including apoptosis, necroptosis, and pyroptosis, integrated as PANoptosis. ZBP1 senses viral Z-RNA and coordinates these death pathways via RHIM-dependent interactions with RIPK3/RIPK1. MLKL-driven membrane rupture during necroptosis activates NLRP3 inflammasome. Caspase-3 can cleave gasdermin E, linking apoptosis to pyroptosis. This integrated cell death ensures viral clearance but can intensify tissue damage.

necroptotic process GO:0070266 programmed necrotic cell death GO:0097300

Show evidence (1 reference)

DOI:10.3390/vetsci11110555 SUPPORT Model Organism

"Influenza A virus (IAV) infection initiates a complex interplay of cell death modalities, including apoptosis, necroptosis, pyroptosis, and their integration, known as PANoptosis, which significantly impacts host immune responses and tissue integrity."

Directly describes PANoptosis as integrated cell death modalities in IAV infection.

Endothelial Dysfunction and Thromboinflammation

Severe influenza involves pulmonary microvascular endothelial infection and activation, leading to vascular leakage, adhesion molecule upregulation (ICAM-1, VCAM-1), and thromboinflammatory complications including venous thromboembolism. In critically ill influenza cohorts, VTE incidence has been reported at 9.37%.

Experimental models

Immune-competent microvascularized lung-on-a-chip (IC-LOC) severe H1N1 model ORGAN ON CHIP The microvascularized interstitial compartment allowed stromal-immune signalling to be measured directly, identifying a fibroblast-derived CXCL12 to CXCR4 axis as the dominant ligand-receptor interaction in the response, and CXCR4 inhibition as a candidate intervention that lowered damage-associated cytokines while preserving antiviral ones.

Downstream

Triggering of Acute Myocardial Infarction The acute systemic inflammatory and prothrombotic state of influenza acts as a trigger for acute myocardial infarction in the first week after infection.

Show evidence (1 reference)

DOI:10.1177/10760296241278615 SUPPORT Human Clinical

"A total of 854 patients with severe influenza were included in the analysis. The incidence of VTE was 9.37% (80/854)."

Quantifies VTE incidence in critically ill influenza patients.

Triggering of Acute Myocardial Infarction

Acute influenza is a recognized short-term trigger of acute myocardial infarction. Influenza-driven systemic inflammation, endothelial activation, platelet activation, and a procoagulant shift can destabilize vulnerable coronary atherosclerotic plaque and precipitate atherothrombotic occlusion, with the excess risk concentrated in the first 7 days after infection. In a self-controlled case-series of laboratory-confirmed influenza, the incidence of hospitalization for acute myocardial infarction was about six-fold higher during the 7-day risk interval than during the control interval, with no increased incidence after day 7. This makes acute MI an important downstream cardiovascular sequela of influenza beyond the respiratory tract, and underpins the cardioprotective rationale for influenza vaccination.

coronary endothelial cell CL:0000115 platelet CL:0000233

inflammatory response GO:0006954 ↑ INCREASED platelet activation GO:0030168 ↑ INCREASED blood coagulation GO:0007596 ↑ INCREASED

heart UBERON:0000948 coronary artery UBERON:0001621

Show evidence (2 references)

PMID:29365305 SUPPORT Human Clinical

"The incidence ratio of an admission for acute myocardial infarction during the risk interval as compared with the control interval was 6.05"

Self-controlled case-series quantifies a ~6-fold increased risk of acute MI in the first 7 days after laboratory-confirmed influenza, establishing influenza as an acute MI trigger.

PMID:29365305 SUPPORT Human Clinical

"Acute myocardial infarction can be triggered by acute respiratory infections."

States the mechanistic premise that acute respiratory infection, including influenza, can trigger acute myocardial infarction.

⬡

Pathograph

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

●

Phenotypes

10

Immune 1

Pneumonia OCCASIONAL HP:0002090

Show evidence (1 reference)

DOI:10.3390/pathogens13070561 SUPPORT Human Clinical

"In some individuals, flu can lead to pneumonia and acute respiratory distress syndrome."

Confirms pneumonia as a serious complication of influenza.

Metabolism 1

Fever VERY_FREQUENT HP:0001945

Fever is a universally recognized cardinal symptom of influenza infection.

Nervous System 1

Headache FREQUENT HP:0002315

Respiratory 4

Cough VERY_FREQUENT HP:0012735

Sore Throat FREQUENT Pharyngitis HP:0025439

Rhinorrhea FREQUENT HP:0031417

Dyspnea OCCASIONAL HP:0002094

Constitutional 3

Myalgia FREQUENT HP:0003326

Fatigue VERY_FREQUENT HP:0012378

Chills FREQUENT HP:0025143

💊

Medical Actions

4

Neuraminidase Inhibitors

Action: neuraminidase inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986

Oseltamivir (oral) and zanamivir (inhaled) inhibit viral neuraminidase, preventing release of new virions from infected cells. Most effective when administered within 48 hours of symptom onset.

Show evidence (2 references)

PMID:29955068 SUPPORT Human Clinical

"Antiviral agents that target the influenza virus enzyme neuraminidase have been developed for prophylaxis and therapy."

Confirms neuraminidase inhibitors as established influenza antivirals.

PMID:41760115 SUPPORT Other

"For seasonal influenza, WHO conditionally recommends treatment within 48 hours of symptom onset with oseltamivir for severe illness, and baloxavir for patients at high risk of progression from non-severe to severe illness."

The WHO influenza clinical practice guidelines conditionally recommend oseltamivir for severe illness within 48 hours of onset.

Cap-Dependent Endonuclease Inhibitor (Baloxavir Marboxil)

Action: baloxavir marboxil therapy Ontology label: Pharmacotherapy NCIT:C15986

Baloxavir marboxil inhibits the cap-dependent endonuclease of the influenza polymerase complex, blocking viral mRNA synthesis. Single-dose oral therapy that has shown faster symptom resolution compared to oseltamivir in real-world studies.

Show evidence (1 reference)

PMID:41760115 SUPPORT Other

"For seasonal influenza, WHO conditionally recommends treatment within 48 hours of symptom onset with oseltamivir for severe illness, and baloxavir for patients at high risk of progression from non-severe to severe illness."

The WHO influenza guidelines conditionally recommend baloxavir for patients at high risk of progression from non-severe to severe illness.

Annual Vaccination

Action: influenza vaccination Ontology label: Vaccination NCIT:C15346

Seasonal influenza vaccination with inactivated, live-attenuated, recombinant, or cell-based vaccines targeting predicted circulating strains is the primary preventive measure.

Show evidence (1 reference)

PMID:29955068 SUPPORT Human Clinical

"Influenza vaccines are formulated every year to match the circulating strains, as they evolve antigenically owing to antigenic drift."

Describes the rationale for annual influenza vaccination.

Supportive Care

Action: Supportive Care NCIT:C15747

Antipyretics, hydration, and rest for mild cases. Mechanical ventilation and intensive care for severe respiratory failure.

🦠

Infectious Agent

2

Influenza A virus

Influenza A viruses are the most clinically significant type, capable of infecting humans, birds, pigs, and other animals. They are classified by hemagglutinin (H) and neuraminidase (N) surface glycoproteins and are responsible for seasonal epidemics and pandemics due to antigenic drift and shift.

Influenza A virus NCBITaxon:11320

Show evidence (1 reference)

PMID:29955068 SUPPORT Human Clinical

"Influenza is an infectious respiratory disease that, in humans, is caused by influenza A and influenza B viruses. Typically characterized by annual seasonal epidemics, sporadic pandemic outbreaks involve influenza A virus strains of zoonotic origin."

Confirms influenza A causes seasonal epidemics and pandemic outbreaks of zoonotic origin.

Influenza B virus

Influenza B viruses primarily infect humans and cause seasonal epidemics. They undergo antigenic drift but not antigenic shift. The Yamagata lineage has not been detected globally since March 2020 and is considered functionally extinct; current vaccines have transitioned to trivalent formulations containing only the Victoria lineage.

Influenza B virus NCBITaxon:11520

Show evidence (1 reference)

PMID:29955068 SUPPORT Human Clinical

"Influenza is an infectious respiratory disease that, in humans, is caused by influenza A and influenza B viruses."

Confirms influenza B as a causative agent of human influenza.

📊

Related Datasets

5

Obesity-associated meta-inflammation alters influenza A antiviral responses in Göttingen minipigs geo:GSE319516

Obesity is a well-recognized risk factor for increased severity following influenza A virus (IAV) infection, likely by promoting meta-inflammation and immune dysregulation, but its effects on antiviral and inflammatory responses remain poorly understood. Using a Göttingen minipig model of diet-induced obesity, we compared antiviral and inflammatory responses before and after IAV infection. Respiratory tract transcriptomics and histopathology revealed no clear obesity-associated immune or inflammatory changes in uninfected minipigs. In contrast, obese pigs showed reduced viral clearance in nasal mucosal tissue accompanied by altered antiviral gene expression pattern four days post infection.

pig BULK RNA SEQ n=25

Identified by GEO DataSets index search for Influenza (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.

single cell sequencing of resting and Influenza-stimulated mononcluear phagocytes of African and Europeans with varying degree of ex-vivo susceptibility to Influenza ega:EGAS00001005000

There is considerable inter-individual immunological and clinical variability upon influenza A virus (IAV) infection in humans; yet, the factors underlying such heterogeneity remain elusive. Here, using an ex vivo cellular model that captures natural variation in the transcriptional responses of monocytes to IAV, we find significant differences in viral mRNA levels between individuals of African and European ancestry. Using single cell analyses, we show that the overall number of cells that will ultimately become infected, rather than the amount of viral transcript expression per cell, is the main driver of the surprisingly higher IAV mRNA levels detected in European cells.

human

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

LC-MS/MS analyses of purified virions of influenza A and B viruses, grown in a range of hosts. massive:MSV000078740

LC-MS/MS analyses of purified virions of influenza A and B viruses, grown in a range of hosts. Described in Hutchinson et al. 'Conserved and host-specific features of influenza virion architecture.'

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 ("Influenza"). Retrieved 2026-08-02.

Interactome of the influenza A virus transcription/replication machinery massive:MSV000078741

Analyses of AP-MS experiments performed in HEK 293T cells infected with the influenza A/WSN/33 virus. In half of the experiments the virus was modified to contain a C-terminal Strep tag on the polymerase subunit PB2. Full details in York et al. 'Interactome analysis of the influenza A virus transcription/replication machinery identifies protein phosphatase 6 as a cellular factor required for efficient virus replication.'

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 ("Influenza"). Retrieved 2026-08-02.

Influenza vaccination in the elderly boosts antibodies against conserved viral proteins and egg-produced glycans massive:MSV000086108

Proteomic analysis of serum IgG antibody repertoire against influenza vaccine H1 (H1N1 A/California/7/2009) and H3 (H3N2 A/Texas/50/2012) in young, middle-aged, and elderly donors vaccinated with Fluzone 2013-14/14-15. Dataset consists of peak-response (days 21-28 post-vaccination) serum IgG samples eluted by affinity chromatography against H1 and H3 vaccine or hemagglutinin and the flow-throughs.

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 ("Influenza"). Retrieved 2026-08-02.

🧫

Experimental Models

1

Immune-competent microvascularized lung-on-a-chip (IC-LOC) severe H1N1 model ORGAN_ON_CHIP namo:OrganOnChip

A microvascularized human small-airway chip carrying both tissue-resident (alveolar macrophage, dendritic cell, interstitial macrophage) and circulating immune populations alongside airway epithelium and stromal fibroblasts. Infection at high multiplicity reproduces the cytokine storm of severe influenza, and single-cell RNA sequencing plus targeted inhibition were used to separate the contributions of individual mediators. Its distinctive result is a dissociation that a cytokine panel alone would not reveal: IL-1beta and TNF-alpha, usually grouped together as pro-inflammatory drivers, act in opposite directions on the storm.

Organism

human NCBITaxon:9606

Tissue

epithelium of bronchiole UBERON:0002051

Culture

Microvascularized immune-competent lung-on-a-chip with airway and interstitial compartments

Publication

PMID:40987954

Pathograph links

Inflammasome Activation and Cytokine Storm recapitulates fidelity: high Severe H1N1 infection produced airway and interstitial cytokine profiles matching those measured in bronchoalveolar lavage fluid from patients with severe influenza. Selective inhibition then established directionality: blocking IL-1beta abolished the storm, whereas blocking TNF-alpha worsened it, identifying TNF-alpha as a regulator rather than a driver.

Limitations: The full immune response required adding circulating immune cells to the resident populations, so the model's fidelity depends on a reconstruction choice rather than on intrinsic tissue composition. It carries no adaptive memory, no systemic organ crosstalk, and a single donor genotype per device, so it cannot address host-genetic variation in severity.

Readouts

Airway and interstitial pro-inflammatory cytokine secretion

Direction: INCREASED

Interpretation: Cytokine elevation matching patient lavage fluid is the primary evidence that the chip reproduces the human storm.

Show evidence (1 reference)

PMID:40987954 SUPPORT In Vitro

"Here we develop an immune-competent, microvascularized, human lung-on-a-chip device to model the small airways, successfully demonstrating the cytokine storm, immune cell activation, epithelial cell damage, and other cellular- and tissue-level human immune responses to severe H1N1 infection."

Reports the cytokine storm and immune activation this readout measures.

Cytokine response to IL-1beta versus TNF-alpha blockade

Direction: ALTERED

Interpretation: Opposite responses to blocking two mediators usually treated together distinguish a driver from a regulator of the storm.

Show evidence (1 reference)

PMID:40987954 SUPPORT In Vitro

"We find that inhibition of IL-1β completely ameliorates the observed cytokine storm, whereas TNF-α appears to be a critical regulator, as its inhibition results in a highly increased inflammatory response."

The inhibition experiment that establishes the opposing roles.

Show evidence (1 reference)

PMID:40987954 SUPPORT In Vitro

"We find that interleukin-1β and tumour necrosis factor-α play opposing roles in the initiation and regulation of the cytokine storm associated with severe influenza."

Supports the chip as informative for the mechanism of the influenza cytokine storm.

Respiratory Epithelial Infection and Cytopathic Effect recapitulates fidelity: moderate H1N1 infection of the airway compartment produced epithelial cell damage alongside viral replication, reproducing the cytopathic effect of severe influenza on human airway epithelium.

Limitations: The model is built on small-airway rather than alveolar epithelium, so it does not capture the alveolar epithelial injury that characterizes fatal influenza pneumonia, and infection is delivered as a single synchronized high-multiplicity inoculum rather than as a spreading infection.

Readouts

Epithelial cell damage after H1N1 infection

Direction: INCREASED

Interpretation: Epithelial damage is the direct cytopathic readout in the airway compartment.

Show evidence (1 reference)

PMID:40987954 SUPPORT In Vitro

"Here we develop an immune-competent, microvascularized, human lung-on-a-chip device to model the small airways, successfully demonstrating the cytokine storm, immune cell activation, epithelial cell damage, and other cellular- and tissue-level human immune responses to severe H1N1 infection."

Reports epithelial cell damage among the recapitulated responses.

Show evidence (1 reference)

PMID:40987954 SUPPORT In Vitro

"However, the full array of tissue-resident and circulatory immune cells is necessary to elicit a significant airway and interstitial cytokine storm in response to severe infection."

Records that the epithelial response is only fully realized with the complete immune reconstruction; PARTIAL reflects that dependence.

Endothelial Dysfunction and Thromboinflammation measures fidelity: moderate The microvascularized interstitial compartment allowed stromal-immune signalling to be measured directly, identifying a fibroblast-derived CXCL12 to CXCR4 axis as the dominant ligand-receptor interaction in the response, and CXCR4 inhibition as a candidate intervention that lowered damage-associated cytokines while preserving antiviral ones.

Limitations: The vascular compartment is a perfused microvascular network without platelets or coagulation factors, so it can report endothelial and stromal signalling but cannot model the thrombotic half of thromboinflammation that this node describes.

Readouts

CXCL12-CXCR4 ligand-receptor interaction in the interstitial compartment

Direction: INCREASED

Interpretation: Fibroblast-derived CXCL12 signalling to immune CXCR4 is the dominant stromal-immune interaction identified in infected devices.

Show evidence (1 reference)

PMID:40987954 SUPPORT In Vitro

"When considering the specific ligand–receptor (L–R) interactions, we found that the CXCL12–CXCR4 interaction had the largest relative contribution in the CXCL pathway, coming largely from fibroblast CXCL12"

Identifies the specific stromal-immune interaction this readout measures.

Show evidence (1 reference)

PMID:40987954 SUPPORT In Vitro

"Furthermore, we discover the critical stromal-immune CXCL12-CXCR4 interaction and its role in immune response to infection."

Supports the chip as a system for measuring stromal-immune signalling in the infected lung interstitium.

{ }

Source YAML

click to show

name: Influenza
creation_date: "2026-03-06T12:00:00Z"
description: >
  Influenza is an acute respiratory infectious disease caused by influenza viruses
  (types A and B in humans), transmitted via respiratory droplets. Influenza A
  and B cause seasonal epidemics, while influenza A is responsible for pandemics due to
  antigenic shift. The WHO estimates annual epidemics result in approximately 1 billion
  infections, 3-5 million cases of severe illness, and 300,000-500,000 deaths globally.
  The disease ranges from mild upper respiratory illness to severe pneumonia, acute
  respiratory distress syndrome, and death, particularly in elderly, immunocompromised,
  and young populations.
category: Infectious Disease
parents:
  - Viral Respiratory Infection
notes: >
  Influenza epidemiology: The WHO estimates annual epidemics result in approximately
  1 billion infections, 3-5 million cases of severe illness, and 300,000-500,000
  deaths globally. The 1918 pandemic resulted in over 40 million deaths worldwide.
  A core 6-gene ISG signature (IFI6, IFI44L, IRF7, ISG15, MX1, MX2) has been
  identified in human lung tissue as an early transcriptomic hallmark of influenza
  infection. Baloxavir resistance surveillance shows low but detectable prevalence of
  PA resistance markers (0.1% in IAV).
disease_term:
  preferred_term: influenza
  term:
    id: MONDO:0005812
    label: influenza
infectious_agent:
  - name: Influenza A virus
    infectious_agent_term:
      preferred_term: Influenza A virus
      term:
        id: NCBITaxon:11320
        label: Influenza A virus
    description: >
      Influenza A viruses are the most clinically significant type, capable of infecting
      humans, birds, pigs, and other animals. They are classified by hemagglutinin (H) and
      neuraminidase (N) surface glycoproteins and are responsible for seasonal epidemics
      and pandemics due to antigenic drift and shift.
    evidence:
      - reference: PMID:29955068
        reference_title: "Influenza."
        supports: SUPPORT
        snippet: "Influenza is an infectious respiratory disease that, in humans, is caused by influenza A and influenza B viruses. Typically characterized by annual seasonal epidemics, sporadic pandemic outbreaks involve influenza A virus strains of zoonotic origin."
        explanation: Confirms influenza A causes seasonal epidemics and pandemic outbreaks of zoonotic origin.
        evidence_source: HUMAN_CLINICAL
  - name: Influenza B virus
    infectious_agent_term:
      preferred_term: Influenza B virus
      term:
        id: NCBITaxon:11520
        label: Influenza B virus
    description: >
      Influenza B viruses primarily infect humans and cause seasonal epidemics. They undergo
      antigenic drift but not antigenic shift. The Yamagata lineage has not been detected
      globally since March 2020 and is considered functionally extinct; current vaccines
      have transitioned to trivalent formulations containing only the Victoria lineage.
    evidence:
      - reference: PMID:29955068
        reference_title: "Influenza."
        supports: SUPPORT
        snippet: "Influenza is an infectious respiratory disease that, in humans, is caused by influenza A and influenza B viruses."
        explanation: Confirms influenza B as a causative agent of human influenza.
        evidence_source: HUMAN_CLINICAL
has_subtypes:
  - name: Seasonal Influenza
    description: Annual epidemics caused by circulating influenza A and B strains undergoing antigenic drift.
    evidence:
      - reference: PMID:29955068
        reference_title: "Influenza."
        supports: SUPPORT
        snippet: "Influenza vaccines are formulated every year to match the circulating strains, as they evolve antigenically owing to antigenic drift."
        explanation: Describes the annual reformulation needed due to antigenic drift driving seasonal epidemics.
        evidence_source: HUMAN_CLINICAL
  - name: Pandemic Influenza
    description: >
      Global outbreaks caused by novel influenza A subtypes to which the population has
      little or no pre-existing immunity, arising from antigenic shift.
    evidence:
      - reference: PMID:29955068
        reference_title: "Influenza."
        supports: SUPPORT
        snippet: "The most severe influenza pandemic, in 1918, resulted in >40 million deaths worldwide."
        explanation: Documents pandemic influenza and its catastrophic potential.
        evidence_source: HUMAN_CLINICAL
  - name: Avian Influenza
    description: >
      Influenza caused by avian-origin influenza A viruses (e.g., H5N1, H7N9) that
      can occasionally infect humans with high case fatality rates.
pathophysiology:
  - name: Respiratory Epithelial Infection and Cytopathic Effect
    description: >
      Influenza viruses bind to sialic acid residues on respiratory epithelial cells
      via hemagglutinin, followed by endocytosis and viral replication in the nucleus.
      Viral neuraminidase facilitates release of new virions. This causes direct cytopathic
      damage to airway epithelium, leading to desquamation, impaired mucociliary
      clearance, and susceptibility to secondary bacterial infection.
    cell_types:
      - preferred_term: respiratory epithelial cell
        term:
          id: CL:0002632
          label: epithelial cell of lower respiratory tract
      - preferred_term: alveolar macrophage
        term:
          id: CL:0000583
          label: alveolar macrophage
    biological_processes:
      - preferred_term: viral genome replication
        term:
          id: GO:0019079
          label: viral genome replication
      - preferred_term: defense response to virus
        term:
          id: GO:0051607
          label: defense response to virus
    locations:
      - preferred_term: lung
        term:
          id: UBERON:0002048
          label: lung
      - preferred_term: respiratory system
        term:
          id: UBERON:0001004
          label: respiratory system
    evidence:
      - reference: DOI:10.3390/pathogens13070561
        reference_title: "Host Innate Antiviral Response to Influenza A Virus Infection: From Viral Sensing to Antagonism and Escape"
        supports: SUPPORT
        snippet: "Influenza virus possesses an RNA genome of single-stranded, negative-sensed, and segmented configuration. Influenza virus causes an acute respiratory disease, commonly known as the \"flu\" in humans. In some individuals, flu can lead to pneumonia and acute respiratory distress syndrome."
        explanation: Describes influenza as an acute respiratory disease caused by viral infection of the respiratory tract.
        evidence_source: HUMAN_CLINICAL
  - name: Toll-like Receptor Signaling and Innate Immune Activation
    conforms_to: "innate_antiviral_interferon_response#Viral PAMP Sensing by Pattern-Recognition Receptors"
    description: >
      Innate immune sensing of influenza occurs through endosomal TLR3, TLR7, and TLR8.
      TLR7/8 signal via MYD88 to activate IRF5/IRF7 and NF-kappaB, while TLR3 signals via
      TRIF to activate IRF3 via TBK1/IKK-epsilon. This dual signaling induces type I and III
      interferons, pro-inflammatory cytokines, and chemokines. The TLR response is a
      double-edged sword: necessary for viral control but capable of driving immunopathology
      when hyperactivated.
    cell_types:
      - preferred_term: dendritic cell
        term:
          id: CL:0000451
          label: dendritic cell
      - preferred_term: macrophage
        term:
          id: CL:0000235
          label: macrophage
      - preferred_term: neutrophil
        term:
          id: CL:0000775
          label: neutrophil
    biological_processes:
      - preferred_term: toll-like receptor signaling pathway
        term:
          id: GO:0002224
          label: toll-like receptor signaling pathway
      - preferred_term: response to type I interferon
        term:
          id: GO:0034340
          label: response to type I interferon
    evidence:
      - reference: DOI:10.3390/ijms25115909
        reference_title: "Recent Insights into the Molecular Mechanisms of the Toll-like Receptor Response to Influenza Virus Infection"
        supports: SUPPORT
        snippet: "Because TLRs may act as a double-edged sword, a balanced TLR response is critical for the overall benefit of the host."
        explanation: Confirms the dual role of TLR signaling in both antiviral defense and immunopathology during influenza.
        evidence_source: IN_VITRO
      - reference: DOI:10.3390/pathogens13070561
        reference_title: "Host Innate Antiviral Response to Influenza A Virus Infection: From Viral Sensing to Antagonism and Escape"
        supports: SUPPORT
        snippet: "Host cells sense IAV infection through multiple receptors and mechanisms, which culminate in the induction of a concerted innate antiviral response and the creation of an antiviral state, which inhibits and clears the infection from host cells."
        explanation: Describes innate antiviral sensing mechanisms including TLR pathways.
        evidence_source: IN_VITRO
  - name: Inflammasome Activation and Cytokine Storm
    description: >
      IAV infection activates NLRP3 and AIM2 inflammasomes. AIM2, canonically a cytosolic
      dsDNA sensor, is activated by host mitochondrial DNA released after IAV-induced
      mitochondrial damage. Inflammasome activation leads to caspase-1-mediated processing
      of IL-1-beta and IL-18, and gasdermin D-mediated pyroptosis. Excessive inflammasome
      activation contributes to the cytokine storm associated with severe influenza.
    cell_types:
      - preferred_term: macrophage
        term:
          id: CL:0000235
          label: macrophage
    biological_processes:
      - preferred_term: pyroptotic inflammatory response
        term:
          id: GO:0070269
          label: pyroptotic inflammatory response
    evidence:
      - reference: DOI:10.3390/v16101535
        reference_title: "Taking AIM at Influenza: The Role of the AIM2 Inflammasome"
        supports: SUPPORT
        snippet: "Paradoxically, AIM2 deficiency has been linked to both enhanced and reduced vulnerability to IAV infection."
        explanation: Describes the complex role of AIM2 inflammasome in influenza pathogenesis.
        evidence_source: MODEL_ORGANISM
      - reference: DOI:10.3390/v16101535
        reference_title: "Taking AIM at Influenza: The Role of the AIM2 Inflammasome"
        supports: SUPPORT
        snippet: "While a strong response is necessary for early viral control, overactivation of inflammasomes can precipitate harmful hyperinflammatory responses, a defining characteristic observed during severe influenza infections."
        explanation: Confirms that inflammasome overactivation drives hyperinflammation in severe influenza.
        evidence_source: MODEL_ORGANISM
  - name: PANoptosis and Inflammatory Cell Death
    description: >
      Influenza A virus triggers multiple regulated cell death pathways including apoptosis,
      necroptosis, and pyroptosis, integrated as PANoptosis. ZBP1 senses viral Z-RNA and
      coordinates these death pathways via RHIM-dependent interactions with RIPK3/RIPK1.
      MLKL-driven membrane rupture during necroptosis activates NLRP3 inflammasome.
      Caspase-3 can cleave gasdermin E, linking apoptosis to pyroptosis. This integrated
      cell death ensures viral clearance but can intensify tissue damage.
    biological_processes:
      - preferred_term: necroptotic process
        term:
          id: GO:0070266
          label: necroptotic process
      - preferred_term: programmed necrotic cell death
        term:
          id: GO:0097300
          label: programmed necrotic cell death
    evidence:
      - reference: DOI:10.3390/vetsci11110555
        reference_title: "Mechanistic Insights into Influenza A Virus-Induced Cell Death and Emerging Treatment Strategies"
        supports: SUPPORT
        snippet: "Influenza A virus (IAV) infection initiates a complex interplay of cell death modalities, including apoptosis, necroptosis, pyroptosis, and their integration, known as PANoptosis, which significantly impacts host immune responses and tissue integrity."
        explanation: Directly describes PANoptosis as integrated cell death modalities in IAV infection.
        evidence_source: MODEL_ORGANISM
  - name: Endothelial Dysfunction and Thromboinflammation
    description: >
      Severe influenza involves pulmonary microvascular endothelial infection and activation,
      leading to vascular leakage, adhesion molecule upregulation (ICAM-1, VCAM-1),
      and thromboinflammatory complications including venous thromboembolism. In critically
      ill influenza cohorts, VTE incidence has been reported at 9.37%.
    evidence:
      - reference: DOI:10.1177/10760296241278615
        reference_title: "Thrombosis in Critically Ill Influenza Patients: Incidence and Risk Factors"
        supports: SUPPORT
        snippet: "A total of 854 patients with severe influenza were included in the analysis. The incidence of VTE was 9.37% (80/854)."
        explanation: Quantifies VTE incidence in critically ill influenza patients.
        evidence_source: HUMAN_CLINICAL
    downstream:
      - target: Triggering of Acute Myocardial Infarction
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        intermediate_mechanisms:
          - Systemic inflammation and thromboinflammatory endothelial activation
          - Coronary atherosclerotic plaque instability and rupture
          - Platelet activation and procoagulant shift causing atherothrombotic coronary occlusion
        description: >
          The acute systemic inflammatory and prothrombotic state of influenza acts as a
          trigger for acute myocardial infarction in the first week after infection.
  - name: Triggering of Acute Myocardial Infarction
    description: >
      Acute influenza is a recognized short-term trigger of acute myocardial infarction.
      Influenza-driven systemic inflammation, endothelial activation, platelet activation,
      and a procoagulant shift can destabilize vulnerable coronary atherosclerotic plaque
      and precipitate atherothrombotic occlusion, with the excess risk concentrated in the
      first 7 days after infection. In a self-controlled case-series of laboratory-confirmed
      influenza, the incidence of hospitalization for acute myocardial infarction was about
      six-fold higher during the 7-day risk interval than during the control interval, with
      no increased incidence after day 7. This makes acute MI an important downstream
      cardiovascular sequela of influenza beyond the respiratory tract, and underpins the
      cardioprotective rationale for influenza vaccination.
    cell_types:
      - preferred_term: coronary endothelial cell
        term:
          id: CL:0000115
          label: endothelial cell
      - preferred_term: platelet
        term:
          id: CL:0000233
          label: platelet
    biological_processes:
      - preferred_term: inflammatory response
        term:
          id: GO:0006954
          label: inflammatory response
        modifier: INCREASED
      - preferred_term: platelet activation
        term:
          id: GO:0030168
          label: platelet activation
        modifier: INCREASED
      - preferred_term: blood coagulation
        term:
          id: GO:0007596
          label: blood coagulation
        modifier: INCREASED
    locations:
      - preferred_term: heart
        term:
          id: UBERON:0000948
          label: heart
      - preferred_term: coronary artery
        term:
          id: UBERON:0001621
          label: coronary artery
    evidence:
      - reference: PMID:29365305
        reference_title: "Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection."
        supports: SUPPORT
        snippet: "The incidence ratio of an admission for acute myocardial infarction during the risk interval as compared with the control interval was 6.05"
        explanation: Self-controlled case-series quantifies a ~6-fold increased risk of acute MI in the first 7 days after laboratory-confirmed influenza, establishing influenza as an acute MI trigger.
        evidence_source: HUMAN_CLINICAL
      - reference: PMID:29365305
        reference_title: "Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection."
        supports: SUPPORT
        snippet: "Acute myocardial infarction can be triggered by acute respiratory infections."
        explanation: States the mechanistic premise that acute respiratory infection, including influenza, can trigger acute myocardial infarction.
        evidence_source: HUMAN_CLINICAL
phenotypes:
  - category: Constitutional
    name: Fever
    description: Acute onset of high fever (38-41 degrees C) is a hallmark of influenza.
    frequency: VERY_FREQUENT
    phenotype_term:
      preferred_term: Fever
      term:
        id: HP:0001945
        label: Fever
    notes: Fever is a universally recognized cardinal symptom of influenza infection.
  - category: Respiratory
    name: Cough
    description: Dry or productive cough is one of the most common symptoms of influenza.
    frequency: VERY_FREQUENT
    phenotype_term:
      preferred_term: Cough
      term:
        id: HP:0012735
        label: Cough
  - category: Constitutional
    name: Myalgia
    description: Diffuse muscle aches are characteristic of influenza infection.
    frequency: FREQUENT
    phenotype_term:
      preferred_term: Myalgia
      term:
        id: HP:0003326
        label: Myalgia
  - category: Constitutional
    name: Headache
    description: Frontal or generalized headache accompanies acute influenza.
    frequency: FREQUENT
    phenotype_term:
      preferred_term: Headache
      term:
        id: HP:0002315
        label: Headache
  - category: Respiratory
    name: Sore Throat
    description: Pharyngitis occurs frequently with influenza infection.
    frequency: FREQUENT
    phenotype_term:
      preferred_term: Sore throat
      term:
        id: HP:0025439
        label: Pharyngitis
  - category: Constitutional
    name: Fatigue
    description: Profound fatigue and malaise may persist for weeks after acute illness.
    frequency: VERY_FREQUENT
    phenotype_term:
      preferred_term: Fatigue
      term:
        id: HP:0012378
        label: Fatigue
  - category: Constitutional
    name: Chills
    description: Rigors and chills frequently accompany the febrile phase.
    frequency: FREQUENT
    phenotype_term:
      preferred_term: Chills
      term:
        id: HP:0025143
        label: Chills
  - category: Respiratory
    name: Rhinorrhea
    description: Nasal congestion and rhinorrhea are common upper respiratory symptoms.
    frequency: FREQUENT
    phenotype_term:
      preferred_term: Rhinorrhea
      term:
        id: HP:0031417
        label: Rhinorrhea
  - category: Respiratory
    name: Dyspnea
    description: Shortness of breath occurs in severe cases, particularly with viral pneumonia.
    frequency: OCCASIONAL
    phenotype_term:
      preferred_term: Dyspnea
      term:
        id: HP:0002094
        label: Dyspnea
  - category: Respiratory
    name: Pneumonia
    description: >
      Primary viral pneumonia or secondary bacterial pneumonia is the most serious
      pulmonary complication and a leading cause of influenza-related mortality.
    frequency: OCCASIONAL
    phenotype_term:
      preferred_term: Pneumonia
      term:
        id: HP:0002090
        label: Pneumonia
    evidence:
      - reference: DOI:10.3390/pathogens13070561
        reference_title: "Host Innate Antiviral Response to Influenza A Virus Infection: From Viral Sensing to Antagonism and Escape"
        supports: SUPPORT
        snippet: "In some individuals, flu can lead to pneumonia and acute respiratory distress syndrome."
        explanation: Confirms pneumonia as a serious complication of influenza.
        evidence_source: HUMAN_CLINICAL
treatments:
  - name: Neuraminidase Inhibitors
    description: >
      Oseltamivir (oral) and zanamivir (inhaled) inhibit viral neuraminidase,
      preventing release of new virions from infected cells. Most effective when
      administered within 48 hours of symptom onset.
    treatment_term:
      preferred_term: neuraminidase inhibitor therapy
      term:
        id: NCIT:C15986
        label: Pharmacotherapy
    evidence:
      - reference: PMID:29955068
        reference_title: "Influenza."
        supports: SUPPORT
        snippet: "Antiviral agents that target the influenza virus enzyme neuraminidase have been developed for prophylaxis and therapy."
        explanation: Confirms neuraminidase inhibitors as established influenza antivirals.
        evidence_source: HUMAN_CLINICAL
      - reference: PMID:41760115
        reference_title: Summary of WHO clinical practice guidelines for influenza.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: "For seasonal influenza, WHO conditionally recommends treatment within 48 hours of symptom onset with oseltamivir for severe illness, and baloxavir for patients at high risk of progression from non-severe to severe illness."
        explanation: The WHO influenza clinical practice guidelines conditionally recommend oseltamivir for severe illness within 48 hours of onset.
  - name: Cap-Dependent Endonuclease Inhibitor (Baloxavir Marboxil)
    description: >
      Baloxavir marboxil inhibits the cap-dependent endonuclease of the influenza
      polymerase complex, blocking viral mRNA synthesis. Single-dose oral therapy
      that has shown faster symptom resolution compared to oseltamivir in real-world studies.
    treatment_term:
      preferred_term: baloxavir marboxil therapy
      term:
        id: NCIT:C15986
        label: Pharmacotherapy
    evidence:
      - reference: PMID:41760115
        reference_title: Summary of WHO clinical practice guidelines for influenza.
        supports: SUPPORT
        evidence_source: OTHER
        snippet: "For seasonal influenza, WHO conditionally recommends treatment within 48 hours of symptom onset with oseltamivir for severe illness, and baloxavir for patients at high risk of progression from non-severe to severe illness."
        explanation: The WHO influenza guidelines conditionally recommend baloxavir for patients at high risk of progression from non-severe to severe illness.
  - name: Annual Vaccination
    description: >
      Seasonal influenza vaccination with inactivated, live-attenuated, recombinant,
      or cell-based vaccines targeting predicted circulating strains is the primary
      preventive measure.
    therapeutic_modality: VACCINE
    treatment_term:
      preferred_term: influenza vaccination
      term:
        id: NCIT:C15346
        label: Vaccination
    evidence:
      - reference: PMID:29955068
        reference_title: "Influenza."
        supports: SUPPORT
        snippet: "Influenza vaccines are formulated every year to match the circulating strains, as they evolve antigenically owing to antigenic drift."
        explanation: Describes the rationale for annual influenza vaccination.
        evidence_source: HUMAN_CLINICAL
  - name: Supportive Care
    description: >
      Antipyretics, hydration, and rest for mild cases. Mechanical ventilation and
      intensive care for severe respiratory failure.
    treatment_term:
      preferred_term: Supportive Care
      term:
        id: NCIT:C15747
        label: Supportive Care
datasets:
- accession: geo:GSE319516
  title: Obesity-associated meta-inflammation alters influenza A antiviral responses in Göttingen minipigs
  description: Obesity is a well-recognized risk factor for increased severity following influenza A virus (IAV) infection, likely by promoting meta-inflammation and immune dysregulation, but its effects on antiviral and inflammatory responses remain poorly understood. Using a Göttingen minipig model of diet-induced obesity, we compared antiviral and inflammatory responses before and after IAV infection. Respiratory tract transcriptomics and histopathology revealed no clear obesity-associated immune or inflammatory changes in uninfected minipigs. In contrast, obese pigs showed reduced viral clearance in nasal mucosal tissue accompanied by altered antiviral gene expression pattern four days post infection.
  organism:
    preferred_term: pig
    term:
      id: NCBITaxon:9823
      label: Sus scrofa
  data_type: BULK_RNA_SEQ
  sample_count: 25
  notes: Identified by GEO DataSets index search for Influenza (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:EGAS00001005000
  title: single cell sequencing of resting and Influenza-stimulated mononcluear phagocytes of African and Europeans with varying degree of ex-vivo susceptibility to Influenza
  description: There is considerable inter-individual immunological and clinical variability upon influenza A virus (IAV) infection in humans; yet, the factors underlying such heterogeneity remain elusive. Here, using an ex vivo cellular model that captures natural variation in the transcriptional responses of monocytes to IAV, we find significant differences in viral mRNA levels between individuals of African and European ancestry. Using single cell analyses, we show that the overall number of cells that will ultimately become infected, rather than the amount of viral transcript expression per cell, is the main driver of the surprisingly higher IAV mRNA levels detected in European cells.
  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 ("Influenza"); 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:MSV000078740
  title: LC-MS/MS analyses of purified virions of influenza A and B viruses, grown in a range of hosts.
  description: LC-MS/MS analyses of purified virions of influenza A and B viruses, grown in a range of hosts. Described in Hutchinson et al. 'Conserved and host-specific features of influenza virion architecture.'
  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 ("Influenza"). Retrieved 2026-08-02.
- accession: massive:MSV000078741
  title: Interactome of the influenza A virus transcription/replication machinery
  description: Analyses of AP-MS experiments performed in HEK 293T cells infected with the influenza A/WSN/33 virus. In half of the experiments the virus was modified to contain a C-terminal Strep tag on the polymerase subunit PB2. Full details in York et al. 'Interactome analysis of the influenza A virus transcription/replication machinery identifies protein phosphatase 6 as a cellular factor required for efficient virus replication.'
  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 ("Influenza"). Retrieved 2026-08-02.
- accession: massive:MSV000086108
  title: Influenza vaccination in the elderly boosts antibodies against conserved viral proteins and egg-produced glycans
  description: Proteomic analysis of serum IgG antibody repertoire against influenza vaccine H1 (H1N1 A/California/7/2009) and H3 (H3N2 A/Texas/50/2012) in young, middle-aged, and elderly donors vaccinated with Fluzone 2013-14/14-15. Dataset consists of peak-response (days 21-28 post-vaccination) serum IgG samples eluted by affinity chromatography against H1 and H3 vaccine or hemagglutinin and the flow-throughs.
  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 ("Influenza"). Retrieved 2026-08-02.

experimental_models:
- name: Immune-competent microvascularized lung-on-a-chip (IC-LOC) severe H1N1 model
  description: >-
    A microvascularized human small-airway chip carrying both tissue-resident
    (alveolar macrophage, dendritic cell, interstitial macrophage) and
    circulating immune populations alongside airway epithelium and stromal
    fibroblasts. Infection at high multiplicity reproduces the cytokine storm of
    severe influenza, and single-cell RNA sequencing plus targeted inhibition
    were used to separate the contributions of individual mediators. Its
    distinctive result is a dissociation that a cytokine panel alone would not
    reveal: IL-1beta and TNF-alpha, usually grouped together as pro-inflammatory
    drivers, act in opposite directions on the storm.
  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: epithelium of bronchiole
    term:
      id: UBERON:0002051
      label: epithelium of bronchiole
  cell_types:
  - preferred_term: Bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  - preferred_term: Alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  - preferred_term: Lung fibroblast
    term:
      id: CL:0002553
      label: fibroblast of lung
  conditions:
  - influenza A H1N1 infection (MOI 10, severe)
  - IL-1beta inhibition (canakinumab)
  - TNF-alpha inhibition (infliximab)
  - CXCR4 inhibition (AMD3100)
  - oseltamivir
  culture_system: Microvascularized immune-competent lung-on-a-chip with airway and interstitial compartments
  publication: PMID:40987954
  modeled_mechanisms:
  - target: Inflammasome Activation and Cytokine Storm
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Severe H1N1 infection produced airway and interstitial cytokine profiles
      matching those measured in bronchoalveolar lavage fluid from patients with
      severe influenza. Selective inhibition then established directionality:
      blocking IL-1beta abolished the storm, whereas blocking TNF-alpha worsened
      it, identifying TNF-alpha as a regulator rather than a driver.
    limitations: >-
      The full immune response required adding circulating immune cells to the
      resident populations, so the model's fidelity depends on a reconstruction
      choice rather than on intrinsic tissue composition. It carries no adaptive
      memory, no systemic organ crosstalk, and a single donor genotype per
      device, so it cannot address host-genetic variation in severity.
    readouts:
    - name: Airway and interstitial pro-inflammatory cytokine secretion
      target: Inflammasome Activation and Cytokine Storm
      direction: INCREASED
      interpretation: >-
        Cytokine elevation matching patient lavage fluid is the primary evidence
        that the chip reproduces the human storm.
      evidence:
      - reference: PMID:40987954
        reference_title: An immune-competent lung-on-a-chip for modelling the human severe influenza infection
          response.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Here we develop an immune-competent, microvascularized, human lung-on-a-chip device to
          model the small airways, successfully demonstrating the cytokine storm, immune cell activation,
          epithelial cell damage, and other cellular- and tissue-level human immune responses to severe
          H1N1 infection.
        explanation: Reports the cytokine storm and immune activation this readout measures.
    - name: Cytokine response to IL-1beta versus TNF-alpha blockade
      target: Inflammasome Activation and Cytokine Storm
      direction: ALTERED
      interpretation: >-
        Opposite responses to blocking two mediators usually treated together
        distinguish a driver from a regulator of the storm.
      evidence:
      - reference: PMID:40987954
        reference_title: An immune-competent lung-on-a-chip for modelling the human severe influenza infection
          response.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: We find that inhibition of IL-1β completely ameliorates the observed cytokine storm, whereas
          TNF-α appears to be a critical regulator, as its inhibition results in a highly increased inflammatory
          response.
        explanation: The inhibition experiment that establishes the opposing roles.
    evidence:
    - reference: PMID:40987954
      reference_title: An immune-competent lung-on-a-chip for modelling the human severe influenza infection
        response.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We find that interleukin-1β and tumour necrosis factor-α play opposing roles in the initiation
        and regulation of the cytokine storm associated with severe influenza.
      explanation: Supports the chip as informative for the mechanism of the influenza cytokine storm.
  - target: Respiratory Epithelial Infection and Cytopathic Effect
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      H1N1 infection of the airway compartment produced epithelial cell damage
      alongside viral replication, reproducing the cytopathic effect of severe
      influenza on human airway epithelium.
    limitations: >-
      The model is built on small-airway rather than alveolar epithelium, so it
      does not capture the alveolar epithelial injury that characterizes fatal
      influenza pneumonia, and infection is delivered as a single synchronized
      high-multiplicity inoculum rather than as a spreading infection.
    readouts:
    - name: Epithelial cell damage after H1N1 infection
      target: Respiratory Epithelial Infection and Cytopathic Effect
      direction: INCREASED
      interpretation: Epithelial damage is the direct cytopathic readout in the airway compartment.
      evidence:
      - reference: PMID:40987954
        reference_title: An immune-competent lung-on-a-chip for modelling the human severe influenza infection
          response.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Here we develop an immune-competent, microvascularized, human lung-on-a-chip device to
          model the small airways, successfully demonstrating the cytokine storm, immune cell activation,
          epithelial cell damage, and other cellular- and tissue-level human immune responses to severe
          H1N1 infection.
        explanation: Reports epithelial cell damage among the recapitulated responses.
    evidence:
    - reference: PMID:40987954
      reference_title: An immune-competent lung-on-a-chip for modelling the human severe influenza infection
        response.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: However, the full array of tissue-resident and circulatory immune cells is necessary to
        elicit a significant airway and interstitial cytokine storm in response to severe infection.
      explanation: Records that the epithelial response is only fully realized with the complete immune
        reconstruction; PARTIAL reflects that dependence.
  - target: Endothelial Dysfunction and Thromboinflammation
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      The microvascularized interstitial compartment allowed stromal-immune
      signalling to be measured directly, identifying a fibroblast-derived
      CXCL12 to CXCR4 axis as the dominant ligand-receptor interaction in the
      response, and CXCR4 inhibition as a candidate intervention that lowered
      damage-associated cytokines while preserving antiviral ones.
    limitations: >-
      The vascular compartment is a perfused microvascular network without
      platelets or coagulation factors, so it can report endothelial and stromal
      signalling but cannot model the thrombotic half of thromboinflammation
      that this node describes.
    readouts:
    - name: CXCL12-CXCR4 ligand-receptor interaction in the interstitial compartment
      target: Endothelial Dysfunction and Thromboinflammation
      direction: INCREASED
      interpretation: >-
        Fibroblast-derived CXCL12 signalling to immune CXCR4 is the dominant
        stromal-immune interaction identified in infected devices.
      evidence:
      - reference: PMID:40987954
        reference_title: An immune-competent lung-on-a-chip for modelling the human severe influenza infection
          response.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: When considering the specific ligand–receptor (L–R) interactions, we found that the CXCL12–CXCR4
          interaction had the largest relative contribution in the CXCL pathway, coming largely from fibroblast
          CXCL12
        explanation: Identifies the specific stromal-immune interaction this readout measures.
    evidence:
    - reference: PMID:40987954
      reference_title: An immune-competent lung-on-a-chip for modelling the human severe influenza infection
        response.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Furthermore, we discover the critical stromal-immune CXCL12-CXCR4 interaction and its role
        in immune response to infection.
      explanation: Supports the chip as a system for measuring stromal-immune signalling in the infected
        lung interstitium.

📚

References & Deep Research

Deep Research

1

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 52 citations 2026-03-06T03:54:22.131615

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

Disease Name: Influenza
MONDO ID: (if available)
Category: Infectious Disease

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Influenza. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Influenza pathophysiology (molecular & cellular mechanisms) — research report (2023–2024 emphasis)

Disease & scope

Disease: Influenza (primarily influenza A virus (IAV), but mechanisms generalize to influenza B in many host-response pathways).
Category: Infectious disease (acute respiratory viral infection).
MONDO ID: Not retrieved in current tool context.

Executive summary

Influenza pathophysiology reflects the coupled dynamics of (i) viral infection/replication in respiratory epithelial cells, (ii) host innate recognition (notably TLR3/7/8 and other PRRs) that drives interferon and inflammatory programs, (iii) inflammasome-driven IL‑1 family cytokine release and inflammatory cell death (pyroptosis/necroptosis/PANoptosis), and (iv) downstream tissue injury including endothelial barrier dysfunction, vascular leakage, and thromboinflammatory complications in severe disease. Recent 2023–2024 human and translational studies sharpen this model by defining cell-type-resolved early lung signatures (e.g., a core 6-gene interferon/ISG module) and by quantifying real-world treatment effects (baloxavir vs oseltamivir) and severe-complication rates (e.g., thrombosis incidence in critically ill cohorts). (an2024hostinnateantiviral pages 1-2, an2024hostinnateantiviral pages 4-5, sohail2024differentialtranscriptomichost pages 10-12, qiu2024thrombosisincritically pages 1-2)

Mechanism / Stage	Key Molecules (HGNC/Viral)	Key Pathways / GO Processes	Key Cellular Components (GO CC)	Key Cell Types (CL)	Anatomical Sites (UBERON)	Representative Evidence (2023–2024)	Source IDs
Viral Entry & Replication	Viral: HA, NA, M2, NP, PA, PB1, PB2; Host: Sialic acid receptors	Viral entry via endocytosis; Viral genome replication; Viral transcription	Endosome; Nucleus; Plasma membrane	Airway epithelial cell (CL:0000066); Macrophage (CL:0000235)	Respiratory tract; Lung	An et al. 2024 (Review): Summarizes viral cycle and 17+ viral proteins modulating host response.	(an2024hostinnateantiviral pages 1-2)
Innate Sensing (TLRs)	TLR3, TLR7, TLR8, TLR4, TLR10; Adaptors: MYD88, TICAM1 (TRIF); TFs: IRF3, IRF7, NFKB1	Toll-like receptor signaling pathway; MyD88-dependent/independent signaling; Cytokine production	Endosome membrane; Cell surface	Dendritic cell; Macrophage; Neutrophil	Lung	Kayesh et al. 2024 (Review): TLR3/7/9 play key antiviral roles; TLR4 senses DAMPs; TLR agonists as adjuvants.	(kayesh2024recentinsightsinto pages 4-5, kayesh2024recentinsightsinto pages 2-4, kayesh2024recentinsightsinto pages 1-2)
Core Interferon & ISG Response	IFI6, IFI44L, IRF7, ISG15, MX1, MX2, CCL8	Response to type I interferon; Defense response to virus; Cytokine-mediated signaling	Cytoplasm; Nucleus	Airway epithelial cell (predominant infection); Macrophage	Lung parenchyma; Bronchus	Sohail et al. 2024 (Primary, Human Lung Explant): Identified 6-gene core ISG signature (IFI6, IFI44L, IRF7, ISG15, MX1, MX2) in early infection.	(sohail2024differentialtranscriptomichost pages 10-12, sohail2024differentialtranscriptomichost pages 1-2)
Inflammasome Activation	NLRP3, AIM2, PYCARD (ASC), CASP1, IL1B, IL18, GSDMD	Inflammasome complex assembly; Pyroptosis; Interleukin-1 beta production	Inflammasome complex; Cytosol	Macrophage; Monocyte	Lung; Respiratory mucosa	Xu & Tate 2024 (Review): AIM2 senses IAV-induced host DNA damage (mtDNA/NETs); drives IL-1β/IL-18 release.	(xu2024takingaimat pages 7-9, kayesh2024recentinsightsinto pages 1-2)
Cell Death (PANoptosis)	ZBP1 (sensor), RIPK1, RIPK3, MLKL, CASP8, CASP3, GSDMD, GSDME	PANoptosis; Necroptosis; Apoptosis; Pyroptosis	Cytosol; Plasma membrane (pore complex)	Infected epithelial cell; Macrophage	Lung epithelium	Sun & Liu 2024 (Review): IAV triggers ZBP1-dependent PANoptosis; crosstalk between death pathways drives immunopathology.	(sun2024mechanisticinsightsinto pages 10-11, sun2024mechanisticinsightsinto pages 11-13, an2024hostinnateantiviral pages 1-2)
Endothelial Dysfunction & Thrombosis	VWF, SELE (P-selectin), F3 (Tissue Factor), IL6, IL1B	Blood coagulation; Platelet activation; Endothelial cell activation; Glycocalyx degradation	Endothelial glycocalyx; Blood microvessel	Pulmonary microvascular endothelial cell; Platelet	Lung vasculature; Systemic vessels	Qiu et al. 2024 (Prospective Cohort): 9.37% VTE incidence in severe flu; aspirin associated with reduced risk (aOR 0.37).	(qiu2024thrombosisincritically pages 2-3, qiu2024thrombosisincritically pages 1-2)
Mucosal Vaccination Response	IL33 (alarmin), IFNG, CXCL10, OASL, DDX58	Mucosal immune response; Compartmentalized antibody production (IgA)	Extracellular space (mucosa); Nasal epithelium	Nasal epithelial cell; CD8+ T cell; cTfh cell	Nasal mucosa	Thwaites et al. 2023 (Primary, Human Challenge): Early nasal IL-33 (<8h) correlates with distinct mucosal antibody response.	(thwaites2023earlymucosalevents pages 9-10, thwaites2023earlymucosalevents pages 2-2, thwaites2023earlymucosalevents pages 1-2)
Real-world Antiviral Therapy	Baloxavir marboxil (target: PA); Oseltamivir (target: NA)	Viral RNA transcription inhibition; Viral release inhibition	Nucleus (PA target); Virion surface (NA target)	Infected host cells	Respiratory tract	Cai et al. 2024 (Real-world Cohort): Baloxavir reduced symptom duration (median 28h vs 48h; aHR 1.35) vs Oseltamivir.	(cai2024realworldeffectivenessand pages 1-2, cai2024realworldeffectivenessand media 252c64e8)

Table: A structured summary of key influenza pathophysiological mechanisms, molecular players, affected cells/tissues, and recent clinical findings extracted from 2023–2024 literature.

1) Core pathophysiology: key concepts and definitions (current understanding)

1.1 Viral tropism and replication

IAV is an enveloped, segmented negative-sense ssRNA virus whose genome is packaged as eight vRNPs with NP and polymerase subunits PA/PB1/PB2; the virion surface contains HA, NA, and M2. HA binds sialic-acid receptors, enabling endocytic entry; vRNPs traffic to the nucleus for transcription/replication; progeny virions bud from the plasma membrane. (an2024hostinnateantiviral pages 1-2)

Mechanistic implication: the need for nuclear replication and the requirement for HA/NA/M2 at distinct lifecycle stages creates multiple intervention points (PA cap-dependent endonuclease inhibition; NA inhibition; host-directed blockade of entry/trafficking). (an2024hostinnateantiviral pages 1-2)

1.2 Innate sensing as a “double-edged sword”

A central concept in modern influenza pathophysiology is that early innate sensing is necessary for viral control but can also drive immunopathology. The innate response can become “hyperactive” and damage host tissues if not properly regulated. (an2024hostinnateantiviral pages 1-2)

2) Primary molecular pathways dysregulated in influenza

2.1 TLR-driven sensing → IRF/NF‑κB programs

Recent 2024 reviews consolidate evidence that endosomal TLRs are major influenza sensors and define canonical signaling routes.

Key mechanistic statement (signal flow): * TLR7/TLR8 signal via MYD88 to activate IRF5/IRF7, AP‑1, and NF‑κB. * TLR3 signals via TRIF (TICAM1) to activate IRF3 (via TBK1/IKKε) and NF‑κB-associated programs. * The consequence is transcription of interferons, cytokines, and pro-inflammatory mediators. (an2024hostinnateantiviral pages 4-5)

Definitions/notes: Kayesh et al. (2024) emphasize that multiple TLRs participate (TLR2/3/4/7/8/9/10) and that TLRs can be “a double-edged sword,” motivating interest in balanced modulation and use of TLR agonists as adjuvants. (kayesh2024recentinsightsinto pages 2-4, kayesh2024recentinsightsinto pages 8-10)

2.2 Interferon and ISG responses as early tissue-scale signatures

A key 2024 human lung explant study (bulk + scRNA-seq) provides direct evidence of early (first 24h) lung antiviral transcriptional programs.

Predominant infected cell types: airway epithelial cells and macrophages. (sohail2024differentialtranscriptomichost pages 1-2)

Core ISG module (6 mRNAs): IFI6, IFI44L, IRF7, ISG15, MX1, MX2. (sohail2024differentialtranscriptomichost pages 1-2)

Additional inflammatory/chemokine signal: infection induced “brisk interferon responses,” with CCL8 described as the most strongly upregulated mRNA. (sohail2024differentialtranscriptomichost pages 1-2)

Pathway-level dysregulation: Gene set enrichment showed induction of IFNα/IFNγ response programs, IL6–JAK–STAT3 signaling, and TNFα signaling via NF‑κB, with suppression of cell-cycle programs (E2F targets). (sohail2024differentialtranscriptomichost pages 8-10)

2.3 Inflammasomes and IL‑1 family cytokines

Inflammasome signaling is increasingly framed as central to severe influenza immunopathology, linking PRR activation, cell death, and IL‑1 family cytokines.

AIM2 inflammasome in influenza

A major 2024 review focuses on AIM2 (Absent in Melanoma 2), canonically a cytosolic dsDNA sensor, but “unexpectedly” implicated in IAV (an RNA virus). (xu2024takingaimat pages 2-4)

Mechanism: IAV-associated host DNA (especially mitochondrial DNA released after mitochondrial damage; also DNA from NETs or phagocytosed material) can activate AIM2, recruiting ASC and caspase-1, leading to IL‑1β/IL‑18 processing and gasdermin-mediated pyroptosis. (xu2024takingaimat pages 7-9, xu2024takingaimat pages 2-4)

Clinical/pathology linkage: excessive IL‑1β/IL‑18 correlates with severity in multiple influenza subtypes; and gasdermin D deficiency is cited as protective in mouse influenza hyperinflammation/lung damage contexts. (xu2024takingaimat pages 2-4)

Important nuance (expert synthesis): AIM2’s role is context-dependent, with “AIM2 deficiency… linked to both enhanced and reduced vulnerability to IAV infection,” suggesting timing/strain/dose and redundancy with other sensors (e.g., cGAS-STING, NLRP3) influence phenotype. (xu2024takingaimat pages 1-2, xu2024takingaimat pages 5-7)

2.4 Programmed cell death and PANoptosis (tissue injury vs viral control)

A 2024 mechanistic review synthesizes how influenza engages apoptosis, necroptosis, pyroptosis, and integrated PANoptosis.

Key sensor: ZBP1 recognizes viral Z-RNA and coordinates apoptosis/necroptosis/pyroptosis via RHIM-dependent interactions with RIPK3/RIPK1. (sun2024mechanisticinsightsinto pages 4-6, sun2024mechanisticinsightsinto pages 6-8)

Necroptosis arm: RIPK1/RIPK3 → MLKL phosphorylation → MLKL oligomerization and pore formation; MLKL-driven membrane rupture can drive potassium efflux that activates NLRP3 inflammasome. (sun2024mechanisticinsightsinto pages 4-6, sun2024mechanisticinsightsinto pages 8-10)

Pyroptosis arm: Inflammasome-activated caspase-1 cleaves GSDMD; caspase-3 can cleave GSDME (linking apoptosis to pyroptosis). (sun2024mechanisticinsightsinto pages 8-10)

Integrated PANoptosis: PANoptosis can “ensure[] the efficient elimination of infected cells while triggering a robust inflammatory response,” illustrating the mechanistic tradeoff between clearance and immunopathology. (sun2024mechanisticinsightsinto pages 11-13)

3) Key molecular players (knowledge-base style)

3.1 Host genes/proteins (examples supported by 2024 sources)

Innate sensing & signaling: TLR3, TLR7, TLR8, MYD88, TICAM1/TRIF, IRF3, IRF7, NFKB1 (an2024hostinnateantiviral pages 4-5, kayesh2024recentinsightsinto pages 2-4)
ISG module / antiviral state: IFI6, IFI44L, IRF7, ISG15, MX1, MX2 (sohail2024differentialtranscriptomichost pages 1-2)
Inflammasome & cytokines: AIM2, NLRP3, PYCARD/ASC, CASP1, IL1B, IL18, GSDMD (xu2024takingaimat pages 2-4, sun2024mechanisticinsightsinto pages 10-11)
Cell death (PANoptosis): ZBP1, RIPK1, RIPK3, MLKL, CASP8, CASP3, GSDME (sun2024mechanisticinsightsinto pages 10-11, sun2024mechanisticinsightsinto pages 4-6)
Endothelial/thromboinflammation: VWF (von Willebrand factor), ICAM1, VCAM1; tissue factor pathway is discussed in thrombosis context (marchenko2024endothelialactivationand pages 12-13, qiu2024thrombosisincritically pages 1-2)

3.2 Viral proteins implicated

HA (entry), NA (release), M2 (ion channel; implicated in inflammasome/mitochondrial perturbation in reviews), polymerase components PA/PB1/PB2 and accessory proteins including NS1 (immune antagonism), PB1-F2 (mitochondrial damage; inflammasome-related context), PA-X (host shutoff context). (an2024hostinnateantiviral pages 1-2, xu2024takingaimat pages 7-9)

3.3 Chemical entities / drugs (real-world and translational)

Baloxavir marboxil (targets viral polymerase acidic (PA) cap-dependent endonuclease). (cai2024realworldeffectivenessand pages 1-2)
Oseltamivir (neuraminidase inhibitor targeting NA). (cai2024realworldeffectivenessand pages 1-2)

4) Key cell types and anatomical locations

4.1 Cell types (with evidence)

Airway epithelial cells and macrophages are identified as predominant IAV host cells early after infection in human lung tissue explants (24h). (sohail2024differentialtranscriptomichost pages 1-2)

Inflammatory responses can occur in bystander cell types with few/no detectable viral transcripts, indicating paracrine cytokine signaling and tissue-level propagation of innate programs. (sohail2024differentialtranscriptomichost pages 1-2)

4.2 Anatomical sites

Nasal mucosa / upper airway: critical for mucosal vaccination responses; LAIV provokes early IL‑33 and subsequent IFN-associated mucosal programs. (thwaites2023earlymucosalevents pages 1-2, thwaites2023earlymucosalevents pages 2-2)
Lower airway / lung parenchyma: key site of viral pneumonia, ISG responses, inflammatory cell recruitment, and cell death-mediated injury. (sohail2024differentialtranscriptomichost pages 1-2, sun2024mechanisticinsightsinto pages 11-13)
Pulmonary microvasculature / endothelium: endothelial infection/activation contributes to leakage and thromboinflammatory complications in severe disease. (marchenko2024endothelialactivationand pages 12-13)

5) Disease progression: sequence of events (stage model)

Exposure & entry: HA binds sialic acid receptors; endocytosis and fusion release vRNPs. (an2024hostinnateantiviral pages 1-2)
Early replication (hours–day 1): nuclear replication/transcription; early innate sensing begins. (an2024hostinnateantiviral pages 1-2)
Innate immune amplification: TLR3/7/8 signaling activates IRFs and NF‑κB, inducing interferons/cytokines and ISGs. (an2024hostinnateantiviral pages 4-5)
Tissue-scale antiviral state: core ISG module (IFI6/IFI44L/IRF7/ISG15/MX1/MX2) emerges as an early hallmark in human lung tissue, with chemokines such as CCL8 prominent. (sohail2024differentialtranscriptomichost pages 1-2)
Inflammasome and inflammatory cell death: AIM2 and NLRP3 pathways process IL‑1β/IL‑18; ZBP1-coordinated PANoptosis links viral nucleic acid sensing to apoptosis/necroptosis/pyroptosis; the combined effect can clear infection but also intensify inflammation. (xu2024takingaimat pages 2-4, sun2024mechanisticinsightsinto pages 11-13)
Barrier dysfunction and systemic complications in severe disease: endothelial activation/dysfunction promotes vascular leakage and supports thrombosis risk; critically ill cohorts show measurable VTE incidence. (marchenko2024endothelialactivationand pages 12-13, qiu2024thrombosisincritically pages 1-2)

6) Phenotypic manifestations (mechanism → phenotype links)

6.1 Respiratory phenotypes

Viral pneumonia / ARDS-like lung injury: driven by cytokine and inflammasome activation and inflammatory cell death; PANoptosis is explicitly linked to “robust inflammatory response” that can contribute to tissue damage. (sun2024mechanisticinsightsinto pages 11-13, xu2024takingaimat pages 1-2)

6.2 Thromboinflammatory phenotypes

A cohort of 854 adults with severe influenza reported VTE incidence 9.37% (80/854); thrombosis was associated with greater requirement for advanced respiratory support (mechanical ventilation, ECMO) and higher co-infection incidence. (qiu2024thrombosisincritically pages 1-2)

Mechanistically, reviews link influenza to endothelial activation and dysfunction, including pulmonary microvascular endothelial infection, leakage, cytokine release, adhesion molecule upregulation (ICAM‑1/VCAM‑1), and NET-associated damage. (marchenko2024endothelialactivationand pages 12-13)

7) Recent developments and real-world implementations (2023–2024)

7.1 Real-world antiviral effectiveness: baloxavir vs oseltamivir

A multicenter real-world ambispective cohort study in outpatient fever clinics in East China (study period 2022.06–2023.06; published 23 July 2024, DOI: https://doi.org/10.3389/fmicb.2024.1428095) enrolled 509 influenza A outpatients.

Key findings: * Median time to alleviation of all influenza symptoms (TTAIS): 28.0 h (baloxavir) vs 48.0 h (oseltamivir). (cai2024realworldeffectivenessand pages 1-2) * Median time to alleviation of fever (TTAF): 18 h vs 30 h. (cai2024realworldeffectivenessand pages 1-2) * Multivariable Cox model: baloxavir associated with faster symptom alleviation (HR ~1.36) and fever resolution (HR ~1.93) compared to oseltamivir. (cai2024realworldeffectivenessand pages 1-2)

The main Kaplan–Meier and adjusted hazard ratio results are visualized in the extracted Figure/Table crops. (cai2024realworldeffectivenessand media 252c64e8, cai2024realworldeffectivenessand media b5b8ace7)

7.2 Antiviral resistance surveillance: baloxavir PA substitutions

A 2024 surveillance analysis of PA sequences in the Americas (published Sep 2024; DOI: https://doi.org/10.2147/DHPS.S470868) analyzed 58,816 IAV and 14,684 IBV PA sequences (up to May 31, 2023).

Key statistics: * IAV: 55/58,816 (0.1%) with resistance markers (~1 in 1000). (acocaljuarez2024baloxavirresistancemarkers pages 2-4) * Most frequent IAV markers: I38V (21), I38M (7), E199G (9). (acocaljuarez2024baloxavirresistancemarkers pages 2-4) * IBV: 8/14,684 (0.05%) with markers; M34I (5) and I38V (3). (acocaljuarez2024baloxavirresistancemarkers pages 4-7)

Clinical relevance emphasized: I38M is described as causing about a tenfold reduction in susceptibility, motivating ongoing molecular surveillance (with noted geographic sequencing gaps). (acocaljuarez2024baloxavirresistancemarkers pages 4-7, acocaljuarez2024baloxavirresistancemarkers pages 7-9)

7.3 Vaccine technology trends and mucosal vaccination rationale

A 2024 Clinical Microbiology Reviews overview emphasizes that limitations of current seasonal vaccines (e.g., egg adaptation, moderate effectiveness) motivate new technologies (cell-based, recombinant, adjuvanted/high-dose, LAIV, nucleic-acid vaccines including mRNA). (clark2024recentadvancesin pages 12-14, clark2024recentadvancesin pages 25-27)

The review notes that LAIV requires intranasal delivery and can elicit mucosal responses (including mucosal IgA), which may better prevent infection at the point of entry; it also summarizes effectiveness/effect size examples (e.g., LAIV reducing ILI by 31% in cited data; cell-based QIIV reducing lab-confirmed influenza by 54.6% in children). (clark2024recentadvancesin pages 19-22)

7.4 Mechanistic immunology of intranasal LAIV in humans (2023)

A Nature Communications 2023 study (Received 18 May 2023; Accepted 22 Nov 2023; DOI: https://doi.org/10.1038/s41467-023-43842-7) reports that LAIV induces “distinct, compartmentalized, antibody responses in the mucosa and blood,” and identifies early mucosal IL‑33 release within the first 8 hours as associated with these response patterns. The study is registered as NCT04110366. (thwaites2023earlymucosalevents pages 1-2)

8) GO/Cellular component and ontology-oriented curation snippets

Below are curation-ready suggestions (labels; IDs not computed here) aligned with evidence above:

8.1 GO Biological Process candidates (examples)

Toll-like receptor signaling pathway (TLR3/TLR7/TLR8; MYD88/TRIF) (an2024hostinnateantiviral pages 4-5, kayesh2024recentinsightsinto pages 2-4)
Response to type I interferon; interferon-stimulated gene expression (IFI6/IFI44L/IRF7/ISG15/MX1/MX2) (sohail2024differentialtranscriptomichost pages 1-2)
Cytokine-mediated signaling pathway; TNFα signaling via NF‑κB; IL6–JAK–STAT3 signaling (sohail2024differentialtranscriptomichost pages 8-10)
Inflammasome complex assembly; IL‑1β and IL‑18 production (AIM2/NLRP3/ASC/CASP1) (xu2024takingaimat pages 2-4, sun2024mechanisticinsightsinto pages 10-11)
Pyroptosis; necroptosis; apoptosis; PANoptosis (ZBP1/RIPK1/RIPK3/MLKL; caspases; gasdermins) (sun2024mechanisticinsightsinto pages 11-13, sun2024mechanisticinsightsinto pages 8-10)
Blood coagulation / immunothrombosis-like processes; endothelial activation (marchenko2024endothelialactivationand pages 12-13, qiu2024thrombosisincritically pages 1-2)

8.2 GO Cellular Component candidates

Endosome; nucleus (viral entry/nuclear replication) (an2024hostinnateantiviral pages 1-2)
Inflammasome complex; cytosol (AIM2/ASC/CASP1) (xu2024takingaimat pages 2-4)
Plasma membrane pore complex (MLKL, gasdermins) (sun2024mechanisticinsightsinto pages 4-6, sun2024mechanisticinsightsinto pages 8-10)
Endothelial glycocalyx / junctional complexes (barrier dysfunction context) (marchenko2024endothelialactivationand pages 12-13)

8.3 Phenotype (HP) candidates (labels)

Fever; cough; influenza-like illness; viral pneumonia; acute respiratory distress syndrome (ARDS) (inferred linkage to described mechanisms of lung injury and severe respiratory disease) (an2024hostinnateantiviral pages 1-2, xu2024takingaimat pages 1-2)
Venous thromboembolism (VTE) (qiu2024thrombosisincritically pages 1-2)

9) Evidence highlights (direct-quote style snippets)

TLR signaling architecture (MYD88 vs TRIF; IRF3/7/NF‑κB activation) is explicitly summarized in the Pathogens 2024 review excerpt describing Myddosome formation and TRIF→TRAF3→TBK1/IKKε→IRF3 phosphorylation. (an2024hostinnateantiviral pages 4-5)
Human lung early response: the Respiratory Research 2024 paper identifies a 6‑mRNA “core transcriptomic response” (IFI6, IFI44L, IRF7, ISG15, MX1, MX2) and states airway epithelial cells and macrophages are predominant host cells. (sohail2024differentialtranscriptomichost pages 1-2)
AIM2 paradox: “AIM2 deficiency has been linked to both enhanced and reduced vulnerability to IAV infection.” (xu2024takingaimat pages 1-2)
PANoptosis tradeoff: PANoptosis “ensures the efficient elimination of infected cells while triggering a robust inflammatory response.” (sun2024mechanisticinsightsinto pages 11-13)

10) Limitations of this tool-based synthesis (PMID requirement)

Several included sources are clearly peer-reviewed and provide DOIs and journal metadata. However, PMIDs/PMCIDs were not consistently extractable from the provided text snippets within this tool run (e.g., Qiu et al. and Cai et al. excerpts did not contain PubMed identifiers). Where PMIDs are required for curation, the DOIs provided should be used to resolve the PubMed records.

Key recent references (URLs; publication dates from retrieved text)

Cai et al. “Real-world effectiveness and safety of Baloxavir Marboxil or Oseltamivir…” Published 23 Jul 2024. https://doi.org/10.3389/fmicb.2024.1428095 (cai2024realworldeffectivenessand pages 1-2)
Sohail et al. “Differential transcriptomic host responses…” 2024. https://doi.org/10.1186/s12931-024-02988-8 (sohail2024differentialtranscriptomichost pages 1-2)
Kayesh et al. “Recent Insights… TLR response…” Published 29 May 2024. https://doi.org/10.3390/ijms25115909 (kayesh2024recentinsightsinto pages 1-2)
An et al. “Host innate antiviral response…” Published 3 Jul 2024. https://doi.org/10.3390/pathogens13070561 (an2024hostinnateantiviral pages 1-2)
Xu & Tate. “Taking AIM at Influenza…” Sep 2024. https://doi.org/10.3390/v16101535 (xu2024takingaimat pages 1-2)
Sun & Liu. “Mechanistic insights into influenza A virus-induced cell death…” Nov 2024. https://doi.org/10.3390/vetsci11110555 (sun2024mechanisticinsightsinto pages 1-2)
Thwaites et al. “Early mucosal events…” 2023. https://doi.org/10.1038/s41467-023-43842-7 (thwaites2023earlymucosalevents pages 1-2)
Acocal-Juárez et al. “Baloxavir resistance markers…” Sep 2024. https://doi.org/10.2147/DHPS.S470868 (acocaljuarez2024baloxavirresistancemarkers pages 2-4)
Qiu et al. “Thrombosis in Critically Ill Influenza Patients…” 2024. https://doi.org/10.1177/10760296241278615 (qiu2024thrombosisincritically pages 1-2)

References

(an2024hostinnateantiviral pages 1-2): Wenlong An, Simran Lakhina, Jessica Leong, Kartik Rawat, and Matloob Husain. Host innate antiviral response to influenza a virus infection: from viral sensing to antagonism and escape. Pathogens, 13:561, Jul 2024. URL: https://doi.org/10.3390/pathogens13070561, doi:10.3390/pathogens13070561. This article has 18 citations.
(an2024hostinnateantiviral pages 4-5): Wenlong An, Simran Lakhina, Jessica Leong, Kartik Rawat, and Matloob Husain. Host innate antiviral response to influenza a virus infection: from viral sensing to antagonism and escape. Pathogens, 13:561, Jul 2024. URL: https://doi.org/10.3390/pathogens13070561, doi:10.3390/pathogens13070561. This article has 18 citations.
(sohail2024differentialtranscriptomichost pages 10-12): Aaqib Sohail, Fakhar H. Waqas, Peter Braubach, Laurien Czichon, Mohamed Samir, Azeem Iqbal, Leonardo de Araujo, Stephan Pleschka, Michael Steinert, Robert Geffers, and Frank Pessler. Differential transcriptomic host responses in the early phase of viral and bacterial infections in human lung tissue explants ex vivo. Respiratory Research, Oct 2024. URL: https://doi.org/10.1186/s12931-024-02988-8, doi:10.1186/s12931-024-02988-8. This article has 9 citations and is from a domain leading peer-reviewed journal.
(qiu2024thrombosisincritically pages 1-2): Xianming Qiu, Mingjie Liu, Quanzhen Wang, Yuke Zhang, Li Kong, and Lei Zhou. Thrombosis in critically ill influenza patients: incidence and risk factors. Clinical and Applied Thrombosis/Hemostasis, Jan 2024. URL: https://doi.org/10.1177/10760296241278615, doi:10.1177/10760296241278615. This article has 3 citations.
(kayesh2024recentinsightsinto pages 4-5): Mohammad Enamul Hoque Kayesh, Michinori Kohara, and Kyoko Tsukiyama-Kohara. Recent insights into the molecular mechanisms of the toll-like receptor response to influenza virus infection. International Journal of Molecular Sciences, 25:5909, May 2024. URL: https://doi.org/10.3390/ijms25115909, doi:10.3390/ijms25115909. This article has 15 citations.
(kayesh2024recentinsightsinto pages 2-4): Mohammad Enamul Hoque Kayesh, Michinori Kohara, and Kyoko Tsukiyama-Kohara. Recent insights into the molecular mechanisms of the toll-like receptor response to influenza virus infection. International Journal of Molecular Sciences, 25:5909, May 2024. URL: https://doi.org/10.3390/ijms25115909, doi:10.3390/ijms25115909. This article has 15 citations.
(kayesh2024recentinsightsinto pages 1-2): Mohammad Enamul Hoque Kayesh, Michinori Kohara, and Kyoko Tsukiyama-Kohara. Recent insights into the molecular mechanisms of the toll-like receptor response to influenza virus infection. International Journal of Molecular Sciences, 25:5909, May 2024. URL: https://doi.org/10.3390/ijms25115909, doi:10.3390/ijms25115909. This article has 15 citations.
(sohail2024differentialtranscriptomichost pages 1-2): Aaqib Sohail, Fakhar H. Waqas, Peter Braubach, Laurien Czichon, Mohamed Samir, Azeem Iqbal, Leonardo de Araujo, Stephan Pleschka, Michael Steinert, Robert Geffers, and Frank Pessler. Differential transcriptomic host responses in the early phase of viral and bacterial infections in human lung tissue explants ex vivo. Respiratory Research, Oct 2024. URL: https://doi.org/10.1186/s12931-024-02988-8, doi:10.1186/s12931-024-02988-8. This article has 9 citations and is from a domain leading peer-reviewed journal.
(xu2024takingaimat pages 7-9): Dianne W. Xu and Michelle D. Tate. Taking aim at influenza: the role of the aim2 inflammasome. Viruses, 16:1535, Sep 2024. URL: https://doi.org/10.3390/v16101535, doi:10.3390/v16101535. This article has 6 citations.
(sun2024mechanisticinsightsinto pages 10-11): Yuling Sun and Kaituo Liu. Mechanistic insights into influenza a virus-induced cell death and emerging treatment strategies. Veterinary Sciences, 11:555, Nov 2024. URL: https://doi.org/10.3390/vetsci11110555, doi:10.3390/vetsci11110555. This article has 14 citations.
(sun2024mechanisticinsightsinto pages 11-13): Yuling Sun and Kaituo Liu. Mechanistic insights into influenza a virus-induced cell death and emerging treatment strategies. Veterinary Sciences, 11:555, Nov 2024. URL: https://doi.org/10.3390/vetsci11110555, doi:10.3390/vetsci11110555. This article has 14 citations.
(qiu2024thrombosisincritically pages 2-3): Xianming Qiu, Mingjie Liu, Quanzhen Wang, Yuke Zhang, Li Kong, and Lei Zhou. Thrombosis in critically ill influenza patients: incidence and risk factors. Clinical and Applied Thrombosis/Hemostasis, Jan 2024. URL: https://doi.org/10.1177/10760296241278615, doi:10.1177/10760296241278615. This article has 3 citations.
(thwaites2023earlymucosalevents pages 9-10): Ryan S. Thwaites, Ashley S. S. Uruchurtu, Victor Augusti Negri, Megan E. Cole, Nehmat Singh, Nelisa Poshai, David Jackson, Katja Hoschler, Tina Baker, Ian C. Scott, Xavier Romero Ros, Emma Suzanne Cohen, Maria Zambon, Katrina M. Pollock, Trevor T. Hansel, and Peter J. M. Openshaw. Early mucosal events promote distinct mucosal and systemic antibody responses to live attenuated influenza vaccine. Nature Communications, Dec 2023. URL: https://doi.org/10.1038/s41467-023-43842-7, doi:10.1038/s41467-023-43842-7. This article has 56 citations and is from a highest quality peer-reviewed journal.
(thwaites2023earlymucosalevents pages 2-2): Ryan S. Thwaites, Ashley S. S. Uruchurtu, Victor Augusti Negri, Megan E. Cole, Nehmat Singh, Nelisa Poshai, David Jackson, Katja Hoschler, Tina Baker, Ian C. Scott, Xavier Romero Ros, Emma Suzanne Cohen, Maria Zambon, Katrina M. Pollock, Trevor T. Hansel, and Peter J. M. Openshaw. Early mucosal events promote distinct mucosal and systemic antibody responses to live attenuated influenza vaccine. Nature Communications, Dec 2023. URL: https://doi.org/10.1038/s41467-023-43842-7, doi:10.1038/s41467-023-43842-7. This article has 56 citations and is from a highest quality peer-reviewed journal.
(thwaites2023earlymucosalevents pages 1-2): Ryan S. Thwaites, Ashley S. S. Uruchurtu, Victor Augusti Negri, Megan E. Cole, Nehmat Singh, Nelisa Poshai, David Jackson, Katja Hoschler, Tina Baker, Ian C. Scott, Xavier Romero Ros, Emma Suzanne Cohen, Maria Zambon, Katrina M. Pollock, Trevor T. Hansel, and Peter J. M. Openshaw. Early mucosal events promote distinct mucosal and systemic antibody responses to live attenuated influenza vaccine. Nature Communications, Dec 2023. URL: https://doi.org/10.1038/s41467-023-43842-7, doi:10.1038/s41467-023-43842-7. This article has 56 citations and is from a highest quality peer-reviewed journal.
(cai2024realworldeffectivenessand pages 1-2): Jianpeng Cai, Hongyu Wang, Xiaoting Ye, Shengjia Lu, Zhili Tan, Zhonghua Li, Dan Lin, Jiancheng Qian, Xiaoxian Lu, Jiaolong Wan, Jie Wang, Jingwen Ai, Yonglan Pu, Lihong Qu, and Sen Wang. Real-world effectiveness and safety of baloxavir marboxil or oseltamivir in outpatients with uncomplicated influenza a: an ambispective, observational, multi-center study. Frontiers in Microbiology, Jul 2024. URL: https://doi.org/10.3389/fmicb.2024.1428095, doi:10.3389/fmicb.2024.1428095. This article has 11 citations and is from a peer-reviewed journal.
(cai2024realworldeffectivenessand media 252c64e8): Jianpeng Cai, Hongyu Wang, Xiaoting Ye, Shengjia Lu, Zhili Tan, Zhonghua Li, Dan Lin, Jiancheng Qian, Xiaoxian Lu, Jiaolong Wan, Jie Wang, Jingwen Ai, Yonglan Pu, Lihong Qu, and Sen Wang. Real-world effectiveness and safety of baloxavir marboxil or oseltamivir in outpatients with uncomplicated influenza a: an ambispective, observational, multi-center study. Frontiers in Microbiology, Jul 2024. URL: https://doi.org/10.3389/fmicb.2024.1428095, doi:10.3389/fmicb.2024.1428095. This article has 11 citations and is from a peer-reviewed journal.
(kayesh2024recentinsightsinto pages 8-10): Mohammad Enamul Hoque Kayesh, Michinori Kohara, and Kyoko Tsukiyama-Kohara. Recent insights into the molecular mechanisms of the toll-like receptor response to influenza virus infection. International Journal of Molecular Sciences, 25:5909, May 2024. URL: https://doi.org/10.3390/ijms25115909, doi:10.3390/ijms25115909. This article has 15 citations.
(sohail2024differentialtranscriptomichost pages 8-10): Aaqib Sohail, Fakhar H. Waqas, Peter Braubach, Laurien Czichon, Mohamed Samir, Azeem Iqbal, Leonardo de Araujo, Stephan Pleschka, Michael Steinert, Robert Geffers, and Frank Pessler. Differential transcriptomic host responses in the early phase of viral and bacterial infections in human lung tissue explants ex vivo. Respiratory Research, Oct 2024. URL: https://doi.org/10.1186/s12931-024-02988-8, doi:10.1186/s12931-024-02988-8. This article has 9 citations and is from a domain leading peer-reviewed journal.
(xu2024takingaimat pages 2-4): Dianne W. Xu and Michelle D. Tate. Taking aim at influenza: the role of the aim2 inflammasome. Viruses, 16:1535, Sep 2024. URL: https://doi.org/10.3390/v16101535, doi:10.3390/v16101535. This article has 6 citations.
(xu2024takingaimat pages 1-2): Dianne W. Xu and Michelle D. Tate. Taking aim at influenza: the role of the aim2 inflammasome. Viruses, 16:1535, Sep 2024. URL: https://doi.org/10.3390/v16101535, doi:10.3390/v16101535. This article has 6 citations.
(xu2024takingaimat pages 5-7): Dianne W. Xu and Michelle D. Tate. Taking aim at influenza: the role of the aim2 inflammasome. Viruses, 16:1535, Sep 2024. URL: https://doi.org/10.3390/v16101535, doi:10.3390/v16101535. This article has 6 citations.
(sun2024mechanisticinsightsinto pages 4-6): Yuling Sun and Kaituo Liu. Mechanistic insights into influenza a virus-induced cell death and emerging treatment strategies. Veterinary Sciences, 11:555, Nov 2024. URL: https://doi.org/10.3390/vetsci11110555, doi:10.3390/vetsci11110555. This article has 14 citations.
(sun2024mechanisticinsightsinto pages 6-8): Yuling Sun and Kaituo Liu. Mechanistic insights into influenza a virus-induced cell death and emerging treatment strategies. Veterinary Sciences, 11:555, Nov 2024. URL: https://doi.org/10.3390/vetsci11110555, doi:10.3390/vetsci11110555. This article has 14 citations.
(sun2024mechanisticinsightsinto pages 8-10): Yuling Sun and Kaituo Liu. Mechanistic insights into influenza a virus-induced cell death and emerging treatment strategies. Veterinary Sciences, 11:555, Nov 2024. URL: https://doi.org/10.3390/vetsci11110555, doi:10.3390/vetsci11110555. This article has 14 citations.
(marchenko2024endothelialactivationand pages 12-13): Vladimir A. Marchenko and Irina N. Zhilinskaya. Endothelial activation and dysfunction caused by influenza a virus (alphainfluenzavirus influenzae). Voprosy virusologii, 69 6:465-478, Dec 2024. URL: https://doi.org/10.36233/0507-4088-264, doi:10.36233/0507-4088-264. This article has 9 citations.
(cai2024realworldeffectivenessand media b5b8ace7): Jianpeng Cai, Hongyu Wang, Xiaoting Ye, Shengjia Lu, Zhili Tan, Zhonghua Li, Dan Lin, Jiancheng Qian, Xiaoxian Lu, Jiaolong Wan, Jie Wang, Jingwen Ai, Yonglan Pu, Lihong Qu, and Sen Wang. Real-world effectiveness and safety of baloxavir marboxil or oseltamivir in outpatients with uncomplicated influenza a: an ambispective, observational, multi-center study. Frontiers in Microbiology, Jul 2024. URL: https://doi.org/10.3389/fmicb.2024.1428095, doi:10.3389/fmicb.2024.1428095. This article has 11 citations and is from a peer-reviewed journal.
(acocaljuarez2024baloxavirresistancemarkers pages 2-4): Erick Acocal-Juárez, Luis Márquez-Domínguez, Verónica Vallejo-Ruíz, Lilia Cedillo, and Gerardo Santos-López. Baloxavir resistance markers in influenza a and b viruses in the americas. Drug, Healthcare and Patient Safety, 16:105-113, Sep 2024. URL: https://doi.org/10.2147/dhps.s470868, doi:10.2147/dhps.s470868. This article has 2 citations and is from a peer-reviewed journal.
(acocaljuarez2024baloxavirresistancemarkers pages 4-7): Erick Acocal-Juárez, Luis Márquez-Domínguez, Verónica Vallejo-Ruíz, Lilia Cedillo, and Gerardo Santos-López. Baloxavir resistance markers in influenza a and b viruses in the americas. Drug, Healthcare and Patient Safety, 16:105-113, Sep 2024. URL: https://doi.org/10.2147/dhps.s470868, doi:10.2147/dhps.s470868. This article has 2 citations and is from a peer-reviewed journal.
(acocaljuarez2024baloxavirresistancemarkers pages 7-9): Erick Acocal-Juárez, Luis Márquez-Domínguez, Verónica Vallejo-Ruíz, Lilia Cedillo, and Gerardo Santos-López. Baloxavir resistance markers in influenza a and b viruses in the americas. Drug, Healthcare and Patient Safety, 16:105-113, Sep 2024. URL: https://doi.org/10.2147/dhps.s470868, doi:10.2147/dhps.s470868. This article has 2 citations and is from a peer-reviewed journal.
(clark2024recentadvancesin pages 12-14): Tristan W. Clark, John S. Tregoning, Helen Lister, Tiziano Poletti, Femy Amin, and Jonathan S. Nguyen-Van-Tam. Recent advances in the influenza virus vaccine landscape: a comprehensive overview of technologies and trials. Clinical Microbiology Reviews, Dec 2024. URL: https://doi.org/10.1128/cmr.00025-24, doi:10.1128/cmr.00025-24. This article has 12 citations and is from a highest quality peer-reviewed journal.
(clark2024recentadvancesin pages 25-27): Tristan W. Clark, John S. Tregoning, Helen Lister, Tiziano Poletti, Femy Amin, and Jonathan S. Nguyen-Van-Tam. Recent advances in the influenza virus vaccine landscape: a comprehensive overview of technologies and trials. Clinical Microbiology Reviews, Dec 2024. URL: https://doi.org/10.1128/cmr.00025-24, doi:10.1128/cmr.00025-24. This article has 12 citations and is from a highest quality peer-reviewed journal.
(clark2024recentadvancesin pages 19-22): Tristan W. Clark, John S. Tregoning, Helen Lister, Tiziano Poletti, Femy Amin, and Jonathan S. Nguyen-Van-Tam. Recent advances in the influenza virus vaccine landscape: a comprehensive overview of technologies and trials. Clinical Microbiology Reviews, Dec 2024. URL: https://doi.org/10.1128/cmr.00025-24, doi:10.1128/cmr.00025-24. This article has 12 citations and is from a highest quality peer-reviewed journal.
(sun2024mechanisticinsightsinto pages 1-2): Yuling Sun and Kaituo Liu. Mechanistic insights into influenza a virus-induced cell death and emerging treatment strategies. Veterinary Sciences, 11:555, Nov 2024. URL: https://doi.org/10.3390/vetsci11110555, doi:10.3390/vetsci11110555. This article has 14 citations.

Ask OpenScientist

OpenScientist Report

Subtypes

Comorbidities

Pathophysiology

Pathograph

Phenotypes

Medical Actions

Infectious Agent

Related Datasets

Experimental Models

Source YAML

References & Deep Research

Deep Research

Disease Pathophysiology Research Template

Target Disease

Research Objectives

Required Information

1. Core Pathophysiology

2. Key Molecular Players

3. Biological Processes (for GO annotation)

4. Cellular Components

5. Disease Progression

6. Phenotypic Manifestations

Citation Requirements

Output Format

Influenza pathophysiology (molecular & cellular mechanisms) — research report (2023–2024 emphasis)

Disease & scope

Executive summary

1) Core pathophysiology: key concepts and definitions (current understanding)

1.1 Viral tropism and replication

1.2 Innate sensing as a “double-edged sword”

2) Primary molecular pathways dysregulated in influenza

2.1 TLR-driven sensing → IRF/NF‑κB programs

2.2 Interferon and ISG responses as early tissue-scale signatures

2.3 Inflammasomes and IL‑1 family cytokines

AIM2 inflammasome in influenza

2.4 Programmed cell death and PANoptosis (tissue injury vs viral control)

3) Key molecular players (knowledge-base style)

3.1 Host genes/proteins (examples supported by 2024 sources)

3.2 Viral proteins implicated

3.3 Chemical entities / drugs (real-world and translational)

4) Key cell types and anatomical locations

4.1 Cell types (with evidence)

4.2 Anatomical sites

5) Disease progression: sequence of events (stage model)

6) Phenotypic manifestations (mechanism → phenotype links)

6.1 Respiratory phenotypes

6.2 Thromboinflammatory phenotypes

7) Recent developments and real-world implementations (2023–2024)

7.1 Real-world antiviral effectiveness: baloxavir vs oseltamivir

7.2 Antiviral resistance surveillance: baloxavir PA substitutions

7.3 Vaccine technology trends and mucosal vaccination rationale

7.4 Mechanistic immunology of intranasal LAIV in humans (2023)

8) GO/Cellular component and ontology-oriented curation snippets

8.1 GO Biological Process candidates (examples)

8.2 GO Cellular Component candidates

8.3 Phenotype (HP) candidates (labels)

9) Evidence highlights (direct-quote style snippets)

10) Limitations of this tool-based synthesis (PMID requirement)

Key recent references (URLs; publication dates from retrieved text)