Leptospirosis

Infectious MONDO:0005825 Pathograph 24 zoonotic bacterial infection spirochetal infection

Leptospirosis is a zoonotic spirochetal infection caused by pathogenic Leptospira species, with clinical severity ranging from self-limited febrile illness to severe multi-organ dysfunction (including jaundice, pulmonary hemorrhage, and acute kidney injury).

Mappings

Definitions

Inheritance

Histopathology

Genes

Models

🏷

Classifications

Harrison's Chapter

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Definitions

Clinical syndrome definition

Leptospirosis includes a broad clinical spectrum from asymptomatic or influenza-like illness to severe icteric and hemorrhagic multi-organ disease.

CASE_DEFINITION Clinical syndrome in human patients

Show evidence (1 reference)

DOI:10.3390/kidneydial4020006 SUPPORT Human Clinical

"The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance."

Defines the broad severity range and hallmark severe manifestations.

Practical diagnostic framework

Clinical suspicion in exposed patients with acute febrile illness should be followed by laboratory confirmation using serology and/or PCR.

DIAGNOSTIC_CRITERIA Frontline and hospital diagnostic workflow

Show evidence (2 references)

PMID:29621837 SUPPORT Human Clinical

"In patients with risk factors for leptospirosis, a high index of clinical suspicion is important to ensure early diagnosis and treatment."

Supports risk-informed clinical suspicion as the diagnostic entry point.

DOI:10.1371/journal.pntd.0012449 SUPPORT Human Clinical

"Enrollment was based on leptospirosis-compatible clinical syndrome and a positive preliminary serological test, with PCR used to confirm the disease."

Supports serology plus PCR-confirmation workflow.

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Subtypes

Anicteric leptospirosis

Self-limited influenza-like leptospirosis without classic severe icteric complications.

Show evidence (1 reference)

PMID:28722888 SUPPORT Other

"Leptospirosis can cause a self-limiting influenza-like illness or a much more serious disease."

Supports a milder, self-limited clinical subtype.

Severe icteric leptospirosis (Weil disease)

Severe leptospirosis with risk of multi-organ failure and death.

Show evidence (1 reference)

PMID:28722888 SUPPORT Other

"This condition is known as Weil disease, and it can progress to multiorgan failure with the potential for death."

Supports severe icteric leptospirosis as a distinct high-risk subtype.

Severe pulmonary leptospirosis (ARDS-associated)

Severe pulmonary leptospirosis can present with ARDS and require rescue extracorporeal support.

Show evidence (1 reference)

DOI:10.3138/jammi-2023-0033 SUPPORT Human Clinical

"Extracorporeal life support (ECLS) has been used as salvage therapy for severe leptospirosis complicated by acute respiratory distress syndrome (ARDS)."

Supports a pulmonary-critical subtype characterized by ARDS in severe leptospirosis.

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Pathophysiology

VM protein-mediated epithelial barrier disruption

Secreted virulence-modifying proteins exploit host calcium signaling to destabilize epithelial junctions and enable early barrier breach.

epithelial cell link

cell junction organization link ↕ DYSREGULATED tight junction disassembly link ↑ INCREASED

Show evidence (2 references)

PMID:41634022 SUPPORT Model Organism

"We demonstrate that, upon infection, an increase in intracellular calcium triggers tight junction destabilization, by activating the calmodulin and myosin light chain kinase signalization."

Supports a calcium-calmodulin-MLCK mechanism for early epithelial barrier disruption.

PMID:41634022 SUPPORT Model Organism

"We identify two bacterial effectors of the Virulence-Modifying (VM) proteins family, structurally related to toxin-like proteins, that promote modulation of calcium homeostasis and disruption of cell-cell junctions, thereby allowing Leptospira translocation across epithelium barriers, tissue..."

Supports VM proteins as the leptospiral effectors that drive epithelial junctional disruption and barrier breach.

ColA-mediated collagen degradation

Pathogenic Leptospira expresses collagenase activity that degrades host collagen substrates during invasive infection.

collagen catabolic process link ↑ INCREASED

Show evidence (1 reference)

PMID:24277745 SUPPORT In Vitro

"Recombinant or native ColA hydrolyzed all the tested substrates in which type III collagen was the favorite substrate with 2.16 mg/mL Km and 35.6 h(-)(1) Kcat values."

Supports collagenase-mediated degradation of host collagen as a discrete invasive mechanism.

Barrier transcytosis across endothelial and epithelial monolayers

Pathogenic leptospires traverse endothelial and epithelial cell barriers during invasive infection.

endothelial cell link kidney epithelial cell link

transcytosis link ↑ INCREASED

Show evidence (1 reference)

PMID:24277745 SUPPORT In Vitro

"Compared with wild-type strain, ΔcolA mutant displayed much-attenuated transcytosis through HEK293 and HUVEC monolayers"

Supports transcellular passage across epithelial and endothelial barriers as an invasive step.

Hematogenous leptospiral dissemination

Pathogenic Leptospira disseminate through blood during acute systemic infection.

response to molecule of bacterial origin link ↑ INCREASED

blood link

Show evidence (1 reference)

DOI:10.3390/kidneydial4020006 SUPPORT Human Clinical

Supports systemic spread associated with progression to severe disease.

cGAS-STING-dependent type I interferon response

Cytosolic DNA sensing in macrophages triggers cGAS-STING signaling that helps restrain renal colonization during leptospiral infection.

macrophage link

MB21D1 link STING1 link

cGAS-STING signaling pathway link ↑ INCREASED

Show evidence (2 references)

PMID:41499635 SUPPORT In Vitro

"We show that L. interrogans induces a robust type I interferon (IFN) response in human and murine macrophages that is dependent on the cytosolic dsDNA sensor Cyclic GMP-AMP Synthase (cGAS) and the Stimulator of IFN Genes (STING) signaling pathway."

Supports cGAS-STING-dependent interferon signaling in infected macrophages as a discrete mechanistic response.

PMID:41499635 SUPPORT Model Organism

"Further, we show that mice deficient in the IFNα/β receptor subunit 1 (IFNAR1) or STING had higher bacterial burdens and increased renal colonization following infection in vivo suggesting that cGAS-STING-driven type I IFN is required for the host defense against L. interrogans."

Mouse infection data support this pathway as a host-defense mechanism that limits renal colonization.

TLR2 signaling activation in monocytes and macrophages

TLR2-dependent innate signaling is activated in myeloid cells during leptospirosis.

monocyte link macrophage link

TLR2 link

toll-like receptor signaling pathway link ↑ INCREASED

Show evidence (2 references)

DOI:10.1371/journal.pone.0312466 SUPPORT Other

"We assessed the direct TLR2 expression and indirect TLR2 involvement via the secretion/mRNA expression of immune effectors during leptospirosis."

Supports activation of a TLR2-centered innate signaling node.

DOI:10.1371/journal.pone.0312466 PARTIAL Other

"Even though increased TLR2 expression in in-vivo and in-vitro studies was evident, human studies reported mixed results showing that the postulated effect of TLR2 response based on other studies may not be valid for human leptospirosis."

Captures uncertainty in direct translation of model-system TLR2 findings to human disease.

Cytokine and chemokine upregulation

Pro-inflammatory cytokine and chemokine expression increases during acute leptospirosis.

CCL2 link IL1B link

positive regulation of cytokine production link ↑ INCREASED

Show evidence (1 reference)

DOI:10.1371/journal.pone.0312466 SUPPORT Other

"Notably, we observed the secretion/mRNA expression of several cytokines (IL6, IL8, IL-1β, TNFα, IFNγ, IL10, CCL2/MCP-1, CCL10, COX2, CXCL1/KC, CXCL2/MIP2) and immune effectors (hBD2, iNOS, Fibronectin, Oxygen, and Nitrogen reactive species) as key aspects of host TLR2 responses during leptospirosis."

Supports increased inflammatory mediator output as a distinct event.

NLRP3 inflammasome complex assembly

Leptospirosis-associated molecular stimuli activate NLRP3 inflammasome assembly.

NLRP3 link CASP1 link

NLRP3 inflammasome complex assembly link ↑ INCREASED

Show evidence (1 reference)

DOI:10.3390/microorganisms11071695 SUPPORT Other

"Synergistically, multiple molecular stimuli are prompted during the infection, activating inflammasomes and Na/K-ATPase signalosome, leading to pro-inflammatory and metabolic alterations during leptospirosis."

Supports activation of the inflammasome node as a separate mechanistic event.

Increased interleukin-1 beta production

Interleukin-1 beta production increases during innate immune activation in leptospirosis.

IL1B link

interleukin-1 beta production link ↑ INCREASED

Show evidence (1 reference)

DOI:10.1371/journal.pone.0312466 SUPPORT Other

Supports increased IL-1beta production as a discrete inflammatory event.

TolC-mediated factor H recruitment

Leptospiral TolC interacts with factor H and preserves factor H cofactor activity.

Show evidence (1 reference)

DOI:10.1128/iai.00419-24 SUPPORT In Vitro

"Functional assays demonstrated that rTolC-bound FH retained cofactor activity for C3b cleavage, highlighting TolC’s role in complement regulation."

Supports a specific complement-regulatory interaction mediated by TolC.

Reduced membrane attack complex deposition

Complement terminal pathway activity is reduced by TolC-dependent immune evasion.

complement activation link ↓ DECREASED

Show evidence (1 reference)

DOI:10.1128/iai.00419-24 SUPPORT In Vitro

"The rTolC protein inhibited both the alternative and the classical pathway-mediated membrane attack complex (MAC) deposition in vitro."

Supports reduced complement terminal pathway activity as a discrete mechanism.

Persistent tissue colonization by Leptospira

In vitro evidence supports a model in which immune evasion promotes ongoing leptospiral tissue colonization and virulence.

Show evidence (1 reference)

DOI:10.1128/iai.00419-24 SUPPORT In Vitro

"These findings indicate that TolC contributes to leptospiral virulence by promoting host tissue colonization and evading the immune response, presenting it as a potential target for diagnostic and therapeutic strategies."

Supports persistent colonization as a separate virulence step.

Leptospiral GLP engagement of Na/K-ATPase

Leptospiral glycolipoprotein directly targets host Na/K-ATPase.

response to lipopolysaccharide link ↑ INCREASED

Show evidence (1 reference)

DOI:10.3390/microorganisms11071695 SUPPORT Other

"Na/K-ATPase is the molecular target of the leptospiral endotoxin (glycolipoprotein—GLP)."

Supports direct molecular targeting of Na/K-ATPase by leptospiral GLP.

Na/K-ATPase dysfunction in endothelial and kidney epithelial cells

Na/K-ATPase dysfunction in vascular and renal cells drives inflammatory-metabolic dysregulation.

endothelial cell link kidney epithelial cell link

inflammatory response link ↕ DYSREGULATED

Show evidence (2 references)

DOI:10.3390/microorganisms11071695 SUPPORT Other

"Na/K-ATPase dysfunctions on different types of cells give rise to the organ disorders manifested in leptospirosis."

Supports cellular dysfunction as a mechanistic bridge to organ-level injury.

DOI:10.3390/microorganisms11071695 SUPPORT Other

Supports inflammatory-metabolic dysregulation downstream of Na/K-ATPase perturbation.

VE-cadherin adherens junction disruption in endothelial cells

Virulent leptospires disrupt endothelial VE-cadherin localization in adherens junctions, linking host-cell association to vascular barrier injury.

endothelial cell link

adherens junction organization link ↓ DECREASED

Show evidence (2 references)

PMID:41592120 SUPPORT In Vitro

"Additionally, bacterial association with host cells correlates with the loss of VE-cadherin localization in adherens junctions."

Supports endothelial adherens junction disruption as a consequence of leptospiral interaction with host cells.

PMID:41592120 SUPPORT In Vitro

"Our findings indicate that VE-cadherin disruption correlates with P1 + species and the presence of virulence-associated genes."

Supports a link between endothelial junction injury and higher-virulence pathogenic leptospires.

Pulmonary microvascular damage in hemorrhagic leptospirosis

Hemorrhagic leptospirosis is associated with prominent injury to the lung microcirculation.

endothelial cell link

lung link

Show evidence (1 reference)

PMID:23951234 SUPPORT Human Clinical

"Prominent vascular damage was present in the lung microcirculation, with decreased CD34 and preserved aquaporin 1 expression."

Human necropsy data directly support pulmonary microvascular injury as a distinct pathophysiological lesion.

Multi-organ tissue injury in severe leptospirosis

Severe leptospirosis causes clinically significant injury across kidney, liver, and lung.

inflammatory response link ↕ DYSREGULATED

kidney link liver link lung link

Show evidence (2 references)

DOI:10.3390/kidneydial4020006 SUPPORT Human Clinical

Supports severe disease as a distinct multi-organ injury stage.

PMID:17044471 SUPPORT Model Organism

"The autopsy findings revealed severe interstitial nephritis and severe pulmonary hemorrhage."

Hamster model evidence independently recapitulates combined renal and pulmonary tissue injury in severe leptospirosis.

Coagulation derangement in critical leptospirosis

Severe leptospirosis can involve dysregulated coagulation with disseminated intravascular coagulation.

platelet link

blood coagulation link ↕ DYSREGULATED

Show evidence (1 reference)

DOI:10.3138/jammi-2023-0033 SUPPORT Human Clinical

"Additional complications included diffuse intravascular coagulation, necrotizing pancreatitis, and limb ischemia."

Supports a distinct coagulopathy mechanism in critical leptospirosis.

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Pathograph

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

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Phenotypes

Blood 3

Pulmonary hemorrhage OCCASIONAL Pulmonary hemorrhage (HP:0040223)

Show evidence (2 references)

PMID:29621837 SUPPORT Human Clinical

"Delays in treatment could increase the risk of severe complications, including pulmonary haemorrhage, acute renal failure and acute liver failure."

Supports pulmonary hemorrhage as a severe leptospirosis complication.

DOI:10.1371/journal.pntd.0012449 SUPPORT Human Clinical

"The presence of complications was 21.6% (8/37), with pulmonary complications being the most frequent (75.0% 6/8)."

Supports the prominence of pulmonary complications within complicated cases.

Disseminated intravascular coagulation RARE Disseminated intravascular coagulation (HP:0005521)

Show evidence (1 reference)

DOI:10.3138/jammi-2023-0033 SUPPORT Human Clinical

"Additional complications included diffuse intravascular coagulation, necrotizing pancreatitis, and limb ischemia."

Supports DIC as a severe hematologic complication in reported critical cases.

Thrombocytopenia OCCASIONAL Thrombocytopenia (HP:0001873)

Show evidence (1 reference)

clinicaltrials:NCT05413720 SUPPORT Human Clinical

"The research hypothesis is based on a suspected strong involvement of the immune system in the genesis of serious manifestations of the disease (hepatitis, renal failure, thrombocytopenia, intra-alveolar hemorrhage)."

Supports thrombocytopenia as a severe clinical manifestation in human leptospirosis-focused cohorts.

Cardiovascular 1

Conjunctival suffusion FREQUENT Conjunctivitis (HP:0000509)

HPO did not yield a precise conjunctival suffusion term in the local ontology build. HP:0000509 (Conjunctivitis) is retained as the closest available conjunctival abnormality mapping, but conjunctival suffusion is clinically distinct because it classically lacks purulent discharge.

Show evidence (1 reference)

DOI:10.1371/journal.pntd.0012449 SUPPORT Human Clinical

"The most frequent symptoms in patients with a positive PCR test were headache (91.9%; 34/37), chills and sweating (80.6%; 29/37), nausea (75%; 27/37), dizziness (74.3%; 26/37), vomiting (61.1%; 22/37), congestion (56.8%; 21/37), and conjunctival suffusion (51.4%; 19/37)."

Supports conjunctival suffusion as a recurrent ocular sign.

Digestive 3

Nausea FREQUENT Nausea (HP:0002018)

Show evidence (1 reference)

DOI:10.1371/journal.pntd.0012449 SUPPORT Human Clinical

Supports frequent nausea in laboratory-confirmed disease.

Vomiting FREQUENT Vomiting (HP:0002013)

Show evidence (1 reference)

DOI:10.1371/journal.pntd.0012449 SUPPORT Human Clinical

Supports vomiting as a frequent acute phenotype.

Jaundice OCCASIONAL Jaundice (HP:0000952)

Show evidence (2 references)

DOI:10.1371/journal.pntd.0012449 SUPPORT Human Clinical

"The frequency of clinical signs classically described in leptospirosis was low: jaundice (8.3%; 3/36) and anuria/oliguria (21.6%; 8/37)."

Supports lower frequency of jaundice in this prospective confirmed cohort.

DOI:10.3390/kidneydial4020006 SUPPORT Human Clinical

Confirms jaundice as part of severe multi-organ leptospirosis.

Genitourinary 2

Acute kidney injury OCCASIONAL Acute kidney injury (HP:0001919)

Show evidence (2 references)

DOI:10.1371/journal.pntd.0012449 SUPPORT Human Clinical

"Leptospirosis is responsible for various clinical syndromes, classically linked with fever and acute kidney injury."

Supports AKI as a core disease-linked complication.

DOI:10.3390/kidneydial4020006 SUPPORT Human Clinical

Supports AKI as a major component of severe disease requiring intensive support.

Oliguria OCCASIONAL Oliguria (HP:0100520)

Show evidence (1 reference)

DOI:10.1371/journal.pntd.0012449 SUPPORT Human Clinical

"The frequency of clinical signs classically described in leptospirosis was low: jaundice (8.3%; 3/36) and anuria/oliguria (21.6%; 8/37)."

Supports oliguria/anuria as an occasional renal manifestation.

Immune 1

Meningitis OCCASIONAL Meningitis (HP:0001287)

Show evidence (1 reference)

DOI:10.3390/kidneydial4020006 SUPPORT Human Clinical

Supports meningitis as a recognized severe manifestation.

Metabolism 1

Fever VERY_FREQUENT Fever (HP:0001945)

Show evidence (1 reference)

DOI:10.1371/journal.pntd.0012449 SUPPORT Human Clinical

"Leptospirosis is responsible for various clinical syndromes, classically linked with fever and acute kidney injury."

Supports fever as a core clinical phenotype.

Nervous System 1

Headache VERY_FREQUENT Headache (HP:0002315)

Show evidence (1 reference)

DOI:10.1371/journal.pntd.0012449 SUPPORT Human Clinical

Supports very high headache frequency in confirmed cases.

Respiratory 1

Acute respiratory distress syndrome OCCASIONAL Acute respiratory distress syndrome (HP:0033677)

Show evidence (1 reference)

DOI:10.3138/jammi-2023-0033 SUPPORT Human Clinical

"Extracorporeal life support (ECLS) has been used as salvage therapy for severe leptospirosis complicated by acute respiratory distress syndrome (ARDS)."

Supports ARDS as a major severe pulmonary phenotype.

Constitutional 2

Myalgia FREQUENT Myalgia (HP:0003326)

Show evidence (1 reference)

PMID:24450239 SUPPORT Human Clinical

"Other findings were myalgia (78.1%), malaise (74.9%), conjunctival suffusion (59.3%), oliguria (56.6%), diarrhea (39%), and jaundice (38%)."

Supports myalgia as a frequent human clinical manifestation in confirmed leptospirosis.

Chills FREQUENT Chills (HP:0025143)

Show evidence (1 reference)

DOI:10.1371/journal.pntd.0012449 SUPPORT Human Clinical

Supports chills as a frequent constitutional symptom in PCR-confirmed acute disease.

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Treatments

Antibiotic pharmacotherapy

Action: pharmacotherapy MAXO:0000058

Agent: doxycycline ↗ ceftriaxone ↗ benzylpenicillin ↗

Antibiotics are central treatment across mild and severe presentations, with early therapy improving outcomes.

Show evidence (2 references)

DOI:10.3389/fmicb.2024.1403765 SUPPORT Human Clinical

"Emphasis is placed on antibiotic therapy, including recommendations for mild and severe cases, as well as the role of probiotics in modulating the gut microbiota."

Supports antibiotics as first-line treatment across clinical severities.

DOI:10.3390/kidneydial4020006 SUPPORT Human Clinical

"Although early antibiotic treatment is usually effective, in severe cases, it may require renal replacement therapy, invasive mechanical ventilation, vasoactive support, and invasive hemodynamic monitoring, increasing the risk of death."

Supports benefit of early antibiotics and escalation needs in severe disease.

Intensive supportive care for severe leptospirosis

Action: supportive care MAXO:0000950

Severe disease may require multi-organ support including renal replacement therapy and mechanical ventilation.

Show evidence (1 reference)

DOI:10.3390/kidneydial4020006 SUPPORT Human Clinical

Supports ICU-level supportive interventions in severe leptospirosis.

Adjunctive corticosteroid therapy (uncertain benefit)

Action: pharmacotherapy MAXO:0000058

Corticosteroids may help selected severe pulmonary presentations, but current evidence remains inconclusive.

Show evidence (1 reference)

DOI:10.3390/jcm13154310 PARTIAL Human Clinical

"Although some studies suggest potential benefits, particularly for pulmonary complications, the evidence remains inconclusive due to the limited number of studies and their methodological limitations."

Supports only partial confidence for routine corticosteroid use.

Extracorporeal life support rescue

Action: supportive care MAXO:0000950

ECLS/ECMO can be considered as rescue support in severe ARDS and multi-organ failure.

Show evidence (1 reference)

DOI:10.3138/jammi-2023-0033 SUPPORT Human Clinical

"ECLS is a viable rescue strategy in severe leptospirosis, even with established MSOF."

Supports rescue ECLS in selected critically ill patients.

Butyrate adjunctive strategy (preclinical)

Action: dietary intervention MAXO:0000088

Agent: butyrate ↗

Experimental butyrate supplementation improved outcomes in hamster acute leptospirosis models via macrophage ROS-linked killing.

Show evidence (1 reference)

DOI:10.1128/mbio.01906-24 PARTIAL Model Organism

"The depletion of SCFAs by antibiotic cocktail treatment reduced survival time after Leptospira infection while supplementation with butyrate but not acetate or propionate significantly amelioration of leptospirosis."

Supports model-organism evidence for a host-directed adjunctive approach that is not yet validated for standard human care.

Recombinant vaccine strategy development (investigational prevention)

Action: vaccination MAXO:0001017

Recombinant vaccine approaches are under active development but face translational barriers before broad protective use.

Show evidence (1 reference)

DOI:10.3390/pathogens12060787 PARTIAL Other

"However, developing recombinant vaccines for leptospirosis faces various challenges, including selecting the ideal expression platform or delivery system, assessing immunogenicity, selecting adjuvants, establishing vaccine formulation, demonstrating protective efficacy against lethal disease in..."

Supports current investigational status of recombinant vaccine strategies and their unresolved translational constraints.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Leptospirosis:

Acute bacterial sepsis Not Yet Curated MONDO:0005229

Overlapping Features Sepsis is a life-threatening cause of acute undifferentiated fever that overlaps clinically with severe leptospirosis.

Distinguishing Features

Rapid progression with early organ dysfunction markers (e.g., altered consciousness, bleeding, oliguria, and abnormal breathing) signals high short-term mortality risk in AUF presentations.
Requires urgent broad diagnostic and treatment pathways while leptospirosis-specific testing is pending.

Show evidence (2 references)

PMID:36130240 SUPPORT Human Clinical

"BACKGROUND: Acute undifferentiated fever (AUF) ranges from self-limiting illness to life-threatening infections, such as sepsis, malaria, dengue, leptospirosis and rickettsioses. Similar clinical presentation challenges the clinical management."

Supports sepsis as a core disease-level differential in AUF settings where leptospirosis is considered.

PMID:36130240 SUPPORT Human Clinical

"Bleeding, cerebral dysfunction, respiratory failure and oliguria at admission, suggestive of severe organ failure secondary to systemic infection, were predictors of death."

Supports severe systemic infection features that complicate distinction from severe leptospirosis at presentation.

Rickettsioses Not Yet Curated MONDO:0006956

Overlapping Features Rickettsial infections are recognized causes of AUF that may be clinically indistinguishable from leptospirosis at initial presentation.

Distinguishing Features

Shared AUF syndromic presentation commonly necessitates broad tropical fever testing rather than syndrome-based exclusion.

Show evidence (1 reference)

PMID:36130240 SUPPORT Human Clinical

Supports rickettsioses as a specific differential diagnosis within AUF cohorts that include leptospirosis.

Dengue fever MONDO:0005502

Overlapping Features Dengue can closely overlap with leptospirosis in acute undifferentiated fever presentations and regional travel contexts.

Distinguishing Features

In returning-traveler settings, dengue is especially common after Southeast Asia travel.
Overlap with leptospirosis in AUF requires context-aware testing rather than symptom-only separation.

Show evidence (2 references)

PMID:36130240 SUPPORT Human Clinical

Supports dengue as a key overlapping febrile differential in settings where leptospirosis is evaluated.

PMID:35469592 SUPPORT Human Clinical

"Among persons returning from travel to Southeast Asia, dengue fever is the most common infectious disease, affecting 50-160 per 1000 travelers."

Supports dengue as a practical travel-related competing diagnosis in febrile syndromes overlapping leptospirosis.

Plasmodium falciparum malaria Not Yet Curated MONDO:0005920

Overlapping Features Falciparum malaria is a high-priority differential in febrile illness and may overlap clinically with leptospirosis.

Distinguishing Features

In returning travelers, falciparum malaria is a leading cause of fever after sub-Saharan Africa travel.
Early malaria-focused testing is critical in AUF because bedside clinical overlap with leptospirosis is substantial.

Show evidence (2 references)

PMID:36130240 SUPPORT Human Clinical

Supports malaria as a core acute febrile differential alongside leptospirosis.

PMID:35469592 SUPPORT Human Clinical

"Among travelers returning from sub-Saharan Africa, Plasmodium falciparum malaria is the most common cause of fever on presentation to centers for infectious diseases and tropical medicine, affecting approximately 50 per 1000 travelers."

Supports falciparum malaria as a high-priority differential in travel-associated febrile presentations.

📊

Related Datasets

Cathelicidin insufficiency in patients with fatal leptospirosis geo:GSE72946

Human whole-blood transcriptome microarray dataset in acute leptospirosis, designed to identify molecular signatures associated with case fatality.

human MICROARRAY n=33

Conditions: acute leptospirosis convalescent leptospirosis healthy volunteers

PMID:27812211

Show evidence (1 reference)

GEO:GSE72946 SUPPORT Human Clinical

"Whole blood transcriptional profiling of Brazilian patients with acute leptospirosis to identify mechanisms associated with case fatality"

Supports use of this human dataset for severity-linked host-response analyses.

Antibody profile in patients with mild and severe leptospirosis geo:GSE86630

Human antibody-profiling dataset comparing mild and severe leptospirosis to define outcome-associated humoral immune signatures and candidate vaccine or diagnostic targets.

human PROTEOMICS

Conditions: mild leptospirosis severe leptospirosis

Show evidence (1 reference)

GEO:GSE86630 SUPPORT Human Clinical

"the antibodyrepertoire varies in patients with different clinical outcomes"

Supports this dataset as a human severity-stratified immunoprofiling resource relevant to clinical heterogeneity.

A Model System for Studying the Transcriptomic and Physiological Changes Associated with Mammalian Host-Adaptation by Leptospira interrogans Serovar Copenhageni geo:GSE53818

RNA-seq dataset comparing L. interrogans in host-adapted rat DMC conditions versus in vitro culture to identify mammalian host-adaptation programs.

Leptospira interrogans BULK RNA SEQ n=6

Conditions: in vivo host-adapted DMC (rat peritoneal cavity) in vitro cultured leptospires

PMID:24626166

Show evidence (1 reference)

GEO:GSE53818 SUPPORT Model Organism

"To obtain a more faithful representation of how leptospires respond to host-derived signals, we used RNA-Seq to compare the transcriptome of L. interrogans cultivated within dialysis membrane chambers (DMCs) implanted into the peritoneal cavities of rats with that of organisms grown in vitro."

Supports this dataset as a key resource for host-adaptation pathophysiology.

MicroRNA profiles of murine macrophages infected with different strains of Leptospira spp geo:GSE105104

Murine macrophage microRNA profiling dataset contrasting infection by virulent, attenuated, and saprophytic Leptospira strains.

house mouse MICROARRAY n=12

Conditions: non-infected control macrophages virulent-strain infection attenuated-strain infection saprophytic-strain infection

PMID:30129936

Show evidence (1 reference)

GEO:GSE105104 SUPPORT In Vitro

"Here, we suggest that post-transcriptional regulation, mediated by miRNAs, may play a role in host response to infection in leptospirosis in a species and virulence-specific manner."

Supports this dataset for host-cell regulatory response mechanisms.

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Clinical Trials

NCT07127718 PHASE_II RECRUITING

DeLEPTO Project 1 is a phase II trial evaluating CFI-guided risk stratification and adjunctive rescue strategies (plasma transfusion, hemoperfusion, ECMO) for complications of leptospirosis.

Target Phenotypes: Pulmonary hemorrhage ↗

Show evidence (1 reference)

clinicaltrials:NCT07127718 SUPPORT Human Clinical

"The goal of this clinical trial is to learn if complement factor I (CFI) works to predict development of complications in participants with leptospirosis."

Supports an actively recruiting interventional trial focused on complication prediction and management in leptospirosis.

NCT05413720 NOT_APPLICABLE COMPLETED

IMMUNOLEPTO is a completed mechanistic clinical study characterizing innate immune cell and cytokine profiles in acute human leptospirosis.

Target Phenotypes: Acute kidney injury ↗ Pulmonary hemorrhage ↗

Show evidence (1 reference)

clinicaltrials:NCT05413720 SUPPORT Human Clinical

Supports a completed trial directly interrogating immune drivers of severe leptospirosis manifestations.

NCT04034550 NOT_APPLICABLE ACTIVE_NOT_RECRUITING

COLEPT is a prospective hospital-based cohort with one-year follow-up for clinical, bacteriological, and immunological characterization of acute leptospirosis.

Target Phenotypes: Fever ↗

Show evidence (1 reference)

clinicaltrials:NCT04034550 SUPPORT Human Clinical

"COLEPT is a prospective interventional study that intends to better inform about leptospirosis, a neglected zoonotic infectious disease."

Supports an active cohort-style clinical trial infrastructure for longitudinal human leptospirosis phenotyping.

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Literature Summaries

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 34 citations 2026-03-03T11:32:59.249020

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: Leptospirosis
MONDO ID: (if available)
Category: Infectious

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Leptospirosis. 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

Title: Pathophysiology of Leptospirosis (molecular and cellular mechanisms) — 2023–2024 evidence-focused report

Target disease - Disease: Leptospirosis (infectious zoonosis caused by pathogenic Leptospira spp.) (goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5) - MONDO ID: Not retrieved from the current evidence set.

1) Key concepts and definitions (current understanding)

1.1 Disease concept and etiologic agent Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira that are motile, diderm bacteria with an outer envelope containing lipopolysaccharide-like molecules and abundant surface proteins implicated in virulence (e.g., OmpL1, LipL32, LipL41, LipL21, Loa22, LigA). (goncalvesdealbuquerque2023cellularpathophysiologyof pages 2-4)

1.2 Core pathophysiologic framing A mechanistic framework emerging from recent reviews describes leptospirosis as a multi-organ, vascular/inflammatory disease driven by (i) early bacteremia and dissemination, (ii) immune recognition dominated by atypical pattern-recognition pathways (notably TLR2), (iii) host-damaging inflammation (cytokines, inflammasome), and (iv) organ-tropic injury, especially renal proximal tubule colonization with electrolyte transport dysfunction and tubulointerstitial inflammation/fibrosis. (goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5, chou2023leptospirosiskidneydisease pages 1-2, chou2023leptospirosiskidneydisease pages 2-3, goncalvesdealbuquerque2023cellularpathophysiologyof pages 2-4)

1.3 Biphasic clinical-immunologic course A biphasic course is described, with an acute (often ~1 week) phase and an “immunological phase” beginning ~5–14 days after infection, consistent with transition from bacteremia to immune-mediated tissue injury and/or complications. (chou2023leptospirosiskidneydisease pages 1-2)

2) Core pathophysiology: molecular pathways and cellular processes

2.1 Entry, dissemination, and early systemic phase Leptospira can rapidly penetrate the host, produce bacteremia, and disseminate via circulation to spleen, liver, lungs, and kidneys; a cited peak blood load occurs around day 5. (goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5)

2.2 Innate sensing and inflammatory signaling (TLRs, NF-κB, chemokines)

Atypical LPS/LLS signaling bias toward TLR2 Leptospiral LPS-like substances (LLS) have atypical innate immune properties: compared with Enterobacteriaceae LPS, they “do not trigger macrophages via TLR4 but instead signal via TLR2,” and impaired TLR4–TRIF signaling is linked to decreased TRIF/RANTES-dependent nitric oxide and reduced CD40 on dendritic cells, potentially shaping adaptive responses. (goncalvesdealbuquerque2023cellularpathophysiologyof pages 2-4)

TLR2 as a central node (systematic review, 2024) A 2024 systematic review synthesized evidence that TLR2 responses during leptospirosis are associated with increased TLR2 expression and broad cytokine/effector programs, including IL6, IL8, IL-1β, TNFα, IFNγ, IL10, CCL2/MCP-1, COX2, and iNOS/ROS/RNS signatures. (kappagoda2024roleoftolllike pages 1-2)

Renal epithelial inflammatory signaling Kidney-focused evidence indicates that LipL32 (a major outer membrane protein) binds TLR2 on renal tubular epithelial cells and triggers inflammatory signaling (NF-κB/TNF axis) contributing to kidney injury and potentially chronic sequelae. (chou2023leptospirosiskidneydisease pages 1-2)

2.3 Inflammasome activation (NLRP3) and cytokine amplification A leptospiral glycolipoprotein (GLP; described as an endotoxin-like fraction) activates monocytes to secrete TNF-α, IL-10, and IL-6 and increases activation markers (e.g., CD69). GLP can synergize with LPS to induce IL-1β via the NLRP3 inflammasome, supporting an inflammasome-driven amplification loop in severe disease. (goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5) Mechanistically, this integration of bacterial ligands, TLRs, Na/K-ATPase signaling, NF-κB, and NLRP3 is explicitly summarized in the “Na/K-ATPase signalosome” schematic figure. (goncalvesdealbuquerque2023cellularpathophysiologyof media 2494c60d)

2.4 Complement dysregulation and immune evasion (factor H, MAC) A 2024 Infection and Immunity study provides direct mechanistic evidence that a leptospiral TolC outer membrane efflux protein supports complement evasion: recombinant TolC binds factor H (FH) and C3b; “rTolC-bound FH retained cofactor activity for C3b cleavage,” and rTolC inhibited membrane attack complex (MAC) deposition via both alternative and classical complement pathways. Blocking surface TolC reduced FH acquisition and increased MAC deposition on leptospires, consistent with protection from complement-mediated killing. (hota2024unveilingtheimpact pages 1-3)

2.5 Oxidative stress and ROS balance (pathogen defense vs host killing) Pathogenic Leptospira species are described as well equipped to sustain oxidative stress inside hosts; this capacity is considered important for virulence. (osoriorodriguez2024acutekidneyinjury pages 2-4) A 2023 multi-omics infection study identified oxidative stress defense factors (e.g., KatE catalase) as part of the leptospiral arsenal during macrophage interaction and highlighted upregulation of TolC-family proteins and a hemolysin linked to pulmonary hemorrhage. (kavela2023useofan pages 15-17)

3) Key molecular players (pathogen and host) with knowledge-base-style annotations

3.1 Pathogen virulence factors (Leptospira proteins/toxins) — selected, evidence-backed - LipL32: major abundant/immunogenic surface protein; binds TLR2 on renal tubular cells to trigger inflammatory signaling implicated in kidney injury. (chou2023leptospirosiskidneydisease pages 1-2, goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5) - LipL21: (i) shields peptidoglycan from NOD1/NOD2 sensing by preventing muropeptide generation; (ii) is required for acute disease in vivo in a CRISPRi hamster model (avirulent when knocked down). (fernandes2023evaluationofleptospira pages 12-14, goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5) - LipL41: CRISPRi knockdown produced only modest attenuation in one model; transposon mutant reportedly remained virulent (contextual evidence within CRISPRi study). (fernandes2023evaluationofleptospira pages 11-12) - OmpL1: CRISPRi silencing appears lethal/essential in Leptospira, implying a critical role in bacterial viability (and by extension, pathogenesis capacity). (fernandes2023evaluationofleptospira pages 12-14, fernandes2023evaluationofleptospira pages 1-2) - Loa22 (OmpA-like): upregulated during host interaction; described to bind ECM components and TLR2 to induce proinflammatory responses; Loa22 mutants are described as attenuated in animal models (as cited in multi-omics analysis). (kavela2023useofan pages 15-17) - LigA/LigB (leptospiral immunoglobulin-like adhesins): bind extracellular matrix proteins (collagen/laminin/fibronectin/fibrinogen); LigA/LigB were upregulated in LipL32 knockdown virulence remodeling and are considered central adhesins. (kavela2023useofan pages 15-17, goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5, fernandes2023evaluationofleptospira pages 11-12) - TolC: binds factor H and C3b, supports C3b cleavage cofactor activity, and reduces MAC deposition (complement evasion). (hota2024unveilingtheimpact pages 1-3) - GLP (glycolipoprotein; endotoxin-like): cytotoxic membrane injury/vacuolation; inhibits Na/K-ATPase across organs; activates monocytes and synergizes to induce IL-1β via NLRP3 inflammasome. (goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5, osoriorodriguez2024acutekidneyinjury pages 2-4) - Hemolysin SphH: forms pores in mammalian cells, linked to hemorrhage and barrier disruption. (goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5)

3.2 Host genes/proteins (HGNC symbols) and roles in leptospirosis pathophysiology - TLR2 (HGNC: TLR2): central pattern-recognition receptor; associated with broad cytokine/effector induction in leptospirosis models and human studies. (kappagoda2024roleoftolllike pages 1-2) - TLR4 (HGNC: TLR4): human TLR4 recognition of leptospiral LPS is limited/atypical; impaired TLR4–TRIF axis is noted in mechanistic summaries. (goncalvesdealbuquerque2023cellularpathophysiologyof pages 2-4) - NOD1, NOD2 (HGNC: NOD1, NOD2): cytosolic PRRs; LipL21-mediated peptidoglycan shielding blocks NOD1/NOD2 recognition. (fernandes2023evaluationofleptospira pages 12-14, goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5) - NLRP3 (HGNC: NLRP3): inflammasome component; GLP synergy supports IL-1β induction via NLRP3 in mechanistic summaries. (goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5) - IL1B, IL6, TNF, IL10 (HGNC: IL1B, IL6, TNF, IL10): cytokines repeatedly implicated in kidney inflammation and systemic injury signatures. (chou2023leptospirosiskidneydisease pages 1-2, chou2023leptospirosiskidneydisease pages 2-3, kappagoda2024roleoftolllike pages 1-2) - CCL2/MCP-1 (HGNC: CCL2): elevated in leptospirosis kidney disease and in TLR2-linked response signatures. (chou2023leptospirosiskidneydisease pages 2-3, kappagoda2024roleoftolllike pages 1-2) - HAVCR1/KIM-1 (HGNC: HAVCR1) and LCN2/NGAL (HGNC: LCN2): kidney injury biomarkers elevated in leptospirosis-associated kidney injury models and/or patients. (chou2023leptospirosiskidneydisease pages 2-3) - STAT3 (HGNC: STAT3) and TGFB1 (HGNC: TGFB1): implicated in maladaptive repair/fibrosis pathways in leptospirosis kidney disease; AKI-to-CKD transition includes TEC STAT3 activation and TGF-β1/SMAD-associated fibrosis. (osoriorodriguez2024acutekidneyinjury pages 2-4, chou2023leptospirosiskidneydisease pages 2-3) - CFH (HGNC: CFH), C3 (HGNC: C3): complement factors targeted by TolC binding (FH, C3b) to inhibit MAC deposition and promote immune evasion. (hota2024unveilingtheimpact pages 1-3)

3.3 Cell types (Cell Ontology-style labels; examples) and affected processes - Renal proximal tubule epithelial cell: primary niche/lesion site; TLR2-driven inflammation and transporter dysfunction contribute to non-oliguric, hypokalemic AKI patterns. (osoriorodriguez2024acutekidneyinjury pages 2-4, chou2023leptospirosiskidneydisease pages 1-2) - Monocyte/macrophage: phagocytosis with incomplete killing; key source of cytokines; targeted by recent host–microbiome therapeutic concepts increasing ROS-mediated killing. (osoriorodriguez2024acutekidneyinjury pages 2-4, chen2024gutmicrobiotaderivedbutyrate pages 1-2) - Dendritic cell: affected by impaired TLR4–TRIF signaling (e.g., altered CD40 expression) in leptospiral LLS models. (goncalvesdealbuquerque2023cellularpathophysiologyof pages 2-4) - Neutrophil: implicated via immune evasion mechanisms (LipL21-associated functions discussed in CRISPRi study context); pulmonary hemorrhage/ARDS clinical phenotypes often involve neutrophil-driven injury pathways in critical illness contexts. (fernandes2023evaluationofleptospira pages 12-14) - Endothelial cell: vascular barrier disruption and hemorrhage are central in severe disease (e.g., SphH pore formation). (goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5)

3.4 Anatomical locations (UBERON-style labels; examples) - Kidney: proximal tubule, renal interstitium (tubulointerstitial nephritis; fibrosis progression). (osoriorodriguez2024acutekidneyinjury pages 2-4, chou2023leptospirosiskidneydisease pages 2-3) - Liver: hepatic dissemination; LipL21 knockdown reduced liver burdens while still allowing kidney colonization, implying organ-specific dissemination requirements. (fernandes2023evaluationofleptospira pages 12-14) - Lung: ARDS/pulmonary hemorrhage is a severe complication; pulmonary colonization/dissemination is part of early bacteremia and severe phenotypes. (goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5, milovanovic2024extracorporeallifesupport pages 1-2)

3.5 Chemical entities (CHEBI-style identifiers; examples) - Butyrate (short-chain fatty acid): gut microbiota-derived metabolite that improves survival in hamster leptospirosis by enhancing macrophage ROS via HDAC3 inhibition and monocarboxylate transport (MCT). (chen2024gutmicrobiotaderivedbutyrate pages 1-2) - Reactive oxygen species (ROS): host antimicrobial effector enhanced by butyrate; also a stress that pathogenic Leptospira resist via antioxidant systems. (chen2024gutmicrobiotaderivedbutyrate pages 1-2, kavela2023useofan pages 15-17) - Electrolytes (K+, Na+): transporter dysfunction and Na/K-ATPase inhibition contribute to hypokalemia and sodium handling changes. (osoriorodriguez2024acutekidneyinjury pages 2-4)

4) Biological processes (GO-style) disrupted in leptospirosis (examples for annotation) - Innate immune response; Toll-like receptor signaling pathway (TLR2-biased recognition). (goncalvesdealbuquerque2023cellularpathophysiologyof pages 2-4, kappagoda2024roleoftolllike pages 1-2) - Cytokine-mediated signaling pathway (IL-6/TNF/IL-1β/IL-10 axes). (chou2023leptospirosiskidneydisease pages 2-3, kappagoda2024roleoftolllike pages 1-2) - Complement activation and regulation; inhibition of membrane attack complex assembly via pathogen factor-H acquisition. (hota2024unveilingtheimpact pages 1-3) - Inflammasome complex assembly / IL-1β production (NLRP3-linked). (goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5, goncalvesdealbuquerque2023cellularpathophysiologyof media 2494c60d) - Epithelial ion transport and homeostasis (Na/K-ATPase-associated transport dysfunction). (osoriorodriguez2024acutekidneyinjury pages 2-4, goncalvesdealbuquerque2023cellularpathophysiologyof media e2659fea) - Extracellular matrix organization, fibrotic process, and maladaptive repair (TGF-β1/SMAD; Wnt/β-catenin; STAT3-associated TEC injury programs). (chou2023leptospirosiskidneydisease pages 2-3) - Response to oxidative stress (host ROS killing vs leptospiral antioxidant defenses). (chen2024gutmicrobiotaderivedbutyrate pages 1-2, kavela2023useofan pages 15-17)

5) Cellular components (GO-CC-style) where key processes occur - Plasma membrane and outer membrane interface: TLR2 signaling initiated by surface lipoproteins (LipL32), and Na/K-ATPase inhibition/signaling at the plasma membrane. (chou2023leptospirosiskidneydisease pages 1-2, goncalvesdealbuquerque2023cellularpathophysiologyof media e2659fea) - Extracellular space/blood: bacteremia dissemination; complement interactions (FH/C3b/MAC). (goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5, hota2024unveilingtheimpact pages 1-3) - Inflammasome complex (cytosolic): NLRP3-mediated IL-1β induction in immune cells in response to GLP synergy. (goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5, goncalvesdealbuquerque2023cellularpathophysiologyof media 2494c60d)

6) Disease progression (sequence of events)

Stage A: Exposure and penetration Exposure occurs via environmental/animal reservoirs (commonly rodents per reviews), with host penetration followed by rapid systemic spread. (petakh2024corticosteroidtreatmentfor pages 1-2, goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5)

Stage B: Septicemic dissemination and early organ seeding Early bacteremia disseminates leptospires to spleen, liver, lungs, and kidneys; blood burden peaks around day 5 in cited models. (goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5)

Stage C: Organ-specific injury programs Kidney: proximal tubule colonization and tubulointerstitial nephritis drive AKI, with mechanistic contributions from outer membrane proteins and GLP-mediated Na/K-ATPase inhibition and transporter dysfunction, causing electrolyte wasting, polyuria and hemodynamic stress. (osoriorodriguez2024acutekidneyinjury pages 2-4) Progression to CKD: persistent cytokine programs and profibrotic pathways (TGF-β1/SMAD, Wnt/β-catenin; STAT3, TEC arrest/senescence) support maladaptive repair and fibrosis in leptospirosis kidney disease. (chou2023leptospirosiskidneydisease pages 2-3)

Stage D: Severe complications and immune-mediated damage Severe phenotypes include pulmonary hemorrhage/ARDS and Weil’s disease, associated with high mortality; hemorrhage mechanisms include pore-forming hemolysins (SphH) and cytotoxic membrane injury (GLP). (goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5, milovanovic2024extracorporeallifesupport pages 1-2)

7) Phenotypic manifestations (HP-style examples) and mechanistic linkage - Fever/headache/conjunctival suffusion: common in confirmed acute leptospirosis cohorts and consistent with systemic inflammatory response. (uriberestrepo2024clinicalpresentationof pages 1-2) - Acute kidney injury (AKI): frequent complication; linked to proximal tubule colonization, tubulointerstitial nephritis, and Na/K-ATPase / transporter dysfunction; may be non-oliguric and hypokalemic. (chou2023leptospirosiskidneydisease pages 1-2, osoriorodriguez2024acutekidneyinjury pages 2-4) - Jaundice/hepatic dysfunction (Weil’s disease): severe manifestation alongside renal dysfunction; linked to systemic dissemination and inflammatory injury. (petakh2024currenttreatmentoptions pages 1-2) - Pulmonary hemorrhage and ARDS: severe manifestation; in severe disease may have mortality up to ~50% according to ECLS review, and is linked to vascular barrier injury and hemorrhagic mechanisms (e.g., SphH). (milovanovic2024extracorporeallifesupport pages 1-2, goncalvesdealbuquerque2023cellularpathophysiologyof pages 4-5)

8) Recent developments and latest research (prioritizing 2023–2024)

8.1 2024: Complement evasion mechanism via TolC The discovery/characterization of TolC as a factor-H and C3b binding surface protein that inhibits MAC deposition provides a concrete, targetable complement-evasion mechanism supporting systemic persistence and tissue colonization. (hota2024unveilingtheimpact pages 1-3)

8.2 2024: Host–microbiome metabolite axis (butyrate → HDAC3 → ROS) A 2024 mBio study demonstrates that microbiota-derived butyrate improves hamster survival in acute leptospirosis by enhancing macrophage ROS bactericidal activity via an MCT-dependent HDAC3 inhibition mechanism (“butyrate-MCT-HDAC3i-ROS signaling axis”). (chen2024gutmicrobiotaderivedbutyrate pages 1-2)

8.3 2023: Functional genetics (CRISPRi) for virulence factor essentiality CRISPRi knockdown in Leptospira shows that OmpL1 is essential (lethal phenotype when silenced) and LipL21 is essential for acute disease in vivo (avirulent when knocked down), while LipL32 knockdown can paradoxically augment virulence with compensatory upregulation of other virulence factors (e.g., LigA/LigB). (fernandes2023evaluationofleptospira pages 12-14, fernandes2023evaluationofleptospira pages 11-12, fernandes2023evaluationofleptospira pages 1-2)

9) Current applications and real-world implementations (diagnostics, therapy, prevention)

9.1 Diagnostics Recent clinical reviews reiterate that the microscopic agglutination test (MAT) remains the gold-standard and most commonly used diagnostic method, while PCR is more sensitive but less available in low-resource settings. (petakh2024corticosteroidtreatmentfor pages 1-2) A 2024 Colombia prospective study operationalized PCR confirmation in suspected febrile patients and found 37% PCR-confirmation among 100 suspected cases, illustrating real-world diagnostic triage in endemic febrile syndrome settings. (uriberestrepo2024clinicalpresentationof pages 1-2)

9.2 Treatment and supportive care Antibiotic therapy remains first-line; a 2024 treatment mini-review describes real-world variability in antibiotic use and reported commonly used agents (e.g., ceftriaxone, doxycycline, ampicillin, penicillin) and notes doxycycline may reduce duration of infection by ~2 days. (petakh2024currenttreatmentoptions pages 1-2) Adjunctive immunomodulation: a 2024 meta-analysis found corticosteroid evidence remains inconclusive (observational studies suggest possible benefit for pulmonary complications; the single randomized trial showed no significant benefit), highlighting ongoing uncertainty and the need for better trials. (petakh2024corticosteroidtreatmentfor pages 1-2) Rescue therapy for severe ARDS: extracorporeal life support (ECLS/ECMO) is used as salvage therapy; a 2024 narrative review identified 43 reported ECLS-treated cases with overall mortality of 16%, but evidence is limited and subject to bias; pulmonary hemorrhage/ARDS mortality in severe disease can be up to 50%. (milovanovic2024extracorporeallifesupport pages 1-2)

9.3 Vaccines and prevention A 2023 recombinant vaccine review notes that commercial vaccines are mainly inactivated whole-cell formulations used in veterinary contexts, while recombinant vaccine development (e.g., LipL32 and Lig proteins) faces persistent challenges (platform/delivery, adjuvants, correlates of protection, achieving renal clearance/sterile immunity). (oliveira2023challengesandstrategies pages 1-2)

10) Relevant recent statistics and data (2023–2024)

10.1 Global burden Multiple 2024 sources converge on an annual global burden around ~1.03 million cases and ~58,900–60,000 deaths. (petakh2024corticosteroidtreatmentfor pages 1-2, petakh2024currenttreatmentoptions pages 1-2, uriberestrepo2024clinicalpresentationof pages 1-2)

10.2 Clinical phenotype frequencies (2024 cohort) In PCR-confirmed cases in Urabá, Colombia (n=37): headache 91.9%, chills/sweating 80.6%, nausea 75%, dizziness 74.3%, vomiting 61.1%, congestion 56.8%, conjunctival suffusion 51.4%; jaundice 8.3%, anuria/oliguria 21.6%; complications 21.6% with pulmonary complications 75% of those; case fatality 2.7% (1 death). (uriberestrepo2024clinicalpresentationof pages 1-2)

10.3 ECLS/ECMO outcomes (2024 narrative review) ECLS-treated leptospirosis cases (n=43 across reports): overall mortality 16%; acute renal failure requiring renal replacement therapy is a frequent major complication (reported 74% in review context). (milovanovic2024extracorporeallifesupport pages 1-2, milovanovic2024extracorporeallifesupport pages 7-9)

11) Evidence items (PMID-anchored where present in the retrieved evidence) - Leptospiral LPS activates via TLR2: “Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism” (Nature Immunology; PMID: 11276206; DOI: 10.1038/86354). (xie2024neutralizinggutderivedlipopolysaccharide pages 23-23) - Na/K-ATPase/GLP → NLRP3 inflammasome (cited within TLR2 systematic review excerpt): “Downregulation of the Na/K-ATPase pump by leptospiral glycolipoprotein activates the NLRP3 inflammasome.” (J Immunol. 2012; PMID: 22323544; DOI: 10.4049/jimmunol.1101987). (kappagoda2024roleoftolllike pages 21-22)

12) Mechanistic visual evidence The GLP→Na/K-ATPase inhibition model and the integrated Na/K-ATPase signalosome schematic (linking TLRs, NF-κB, and NLRP3) are captured in figures from a 2023 mechanistic review and support the proposed ion-transport/inflammation coupling in leptospirosis pathophysiology. (goncalvesdealbuquerque2023cellularpathophysiologyof media e2659fea, goncalvesdealbuquerque2023cellularpathophysiologyof media 2494c60d)

Limitations of this report (based on available evidence set) - Some organ-specific mechanisms (e.g., detailed endothelial glycocalyx injury pathways; NET-mediated lung microthrombosis; quantitative complement gene associations; comprehensive metabolomics) were not directly extractable from the currently retrieved full-text excerpts and would require targeted retrieval of additional primary pulmonary-vascular studies.

References

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(fernandes2023evaluationofleptospira pages 12-14): Luis G. V. Fernandes, Aline F. Teixeira, and Ana L. T. O. Nascimento. Evaluation of leptospira interrogans knockdown mutants for lipl32, lipl41, lipl21, and ompl1 proteins. Frontiers in Microbiology, Jun 2023. URL: https://doi.org/10.3389/fmicb.2023.1199660, doi:10.3389/fmicb.2023.1199660. This article has 14 citations and is from a peer-reviewed journal.
(fernandes2023evaluationofleptospira pages 11-12): Luis G. V. Fernandes, Aline F. Teixeira, and Ana L. T. O. Nascimento. Evaluation of leptospira interrogans knockdown mutants for lipl32, lipl41, lipl21, and ompl1 proteins. Frontiers in Microbiology, Jun 2023. URL: https://doi.org/10.3389/fmicb.2023.1199660, doi:10.3389/fmicb.2023.1199660. This article has 14 citations and is from a peer-reviewed journal.
(fernandes2023evaluationofleptospira pages 1-2): Luis G. V. Fernandes, Aline F. Teixeira, and Ana L. T. O. Nascimento. Evaluation of leptospira interrogans knockdown mutants for lipl32, lipl41, lipl21, and ompl1 proteins. Frontiers in Microbiology, Jun 2023. URL: https://doi.org/10.3389/fmicb.2023.1199660, doi:10.3389/fmicb.2023.1199660. This article has 14 citations and is from a peer-reviewed journal.
(chen2024gutmicrobiotaderivedbutyrate pages 1-2): Xi Chen, Xufeng Xie, Ni Sun, Xin Liu, Jiuxi Liu, Wenlong Zhang, and Yongguo Cao. Gut microbiota-derived butyrate improved acute leptospirosis in hamster via promoting macrophage ros mediated by hdac3 inhibition. Oct 2024. URL: https://doi.org/10.1128/mbio.01906-24, doi:10.1128/mbio.01906-24. This article has 7 citations and is from a domain leading peer-reviewed journal.
(milovanovic2024extracorporeallifesupport pages 1-2): Lazar Milovanovic, Gurmeet Singh, Derek Townsend, Jayan Nagendran, and Wendy Sligl. Extracorporeal life support for severe leptospirosis: case series and narrative review. Journal of the Association of Medical Microbiology and Infectious Disease Canada, Sep 2024. URL: https://doi.org/10.3138/jammi-2023-0033, doi:10.3138/jammi-2023-0033. This article has 5 citations.
(goncalvesdealbuquerque2023cellularpathophysiologyof media e2659fea): Cassiano Felippe Gonçalves-de-Albuquerque, Carolina Medina Coeli da Cunha, Léo Victor Grimaldi de Castro, Caroline de Azevedo Martins, Marcos Roberto Colombo Barnese, Patrícia Burth, and Mauricio Younes-Ibrahim. Cellular pathophysiology of leptospirosis: role of na/k-atpase. Microorganisms, 11:1695, Jun 2023. URL: https://doi.org/10.3390/microorganisms11071695, doi:10.3390/microorganisms11071695. This article has 20 citations.
(petakh2024corticosteroidtreatmentfor pages 1-2): Pavlo Petakh, Valentyn Oksenych, and Oleksandr Kamyshnyi. Corticosteroid treatment for leptospirosis: a systematic review and meta-analysis. Journal of Clinical Medicine, 13:4310, Jul 2024. URL: https://doi.org/10.3390/jcm13154310, doi:10.3390/jcm13154310. This article has 11 citations.
(uriberestrepo2024clinicalpresentationof pages 1-2): Pablo Uribe-Restrepo, Janeth Perez-Garcia, Margarita Arboleda, Claudia Munoz-Zanzi, and Piedad Agudelo-Florez. Clinical presentation of human leptospirosis in febrile patients: urabá, colombia. Sep 2024. URL: https://doi.org/10.1371/journal.pntd.0012449, doi:10.1371/journal.pntd.0012449. This article has 12 citations and is from a domain leading peer-reviewed journal.
(petakh2024currenttreatmentoptions pages 1-2): Pavlo Petakh, Payam Behzadi, Valentyn Oksenych, and Oleksandr Kamyshnyi. Current treatment options for leptospirosis: a mini-review. Frontiers in Microbiology, Apr 2024. URL: https://doi.org/10.3389/fmicb.2024.1403765, doi:10.3389/fmicb.2024.1403765. This article has 51 citations and is from a peer-reviewed journal.
(oliveira2023challengesandstrategies pages 1-2): Natasha Rodrigues de Oliveira, Francisco Denis Souza Santos, Vitória Adrielly Catschor dos Santos, Mara Andrade Colares Maia, Thaís Larré Oliveira, and Odir Antônio Dellagostin. Challenges and strategies for developing recombinant vaccines against leptospirosis: role of expression platforms and adjuvants in achieving protective efficacy. Pathogens, 12:787, May 2023. URL: https://doi.org/10.3390/pathogens12060787, doi:10.3390/pathogens12060787. This article has 15 citations.
(milovanovic2024extracorporeallifesupport pages 7-9): Lazar Milovanovic, Gurmeet Singh, Derek Townsend, Jayan Nagendran, and Wendy Sligl. Extracorporeal life support for severe leptospirosis: case series and narrative review. Journal of the Association of Medical Microbiology and Infectious Disease Canada, Sep 2024. URL: https://doi.org/10.3138/jammi-2023-0033, doi:10.3138/jammi-2023-0033. This article has 5 citations.
(xie2024neutralizinggutderivedlipopolysaccharide pages 23-23): Xufeng Xie, Xi Chen, Shilei Zhang, Jiuxi Liu, Wenlong Zhang, and Yongguo Cao. Neutralizing gut-derived lipopolysaccharide as a novel therapeutic strategy for severe leptospirosis. May 2024. URL: https://doi.org/10.7554/elife.96065.2, doi:10.7554/elife.96065.2. This article has 11 citations.
(kappagoda2024roleoftolllike pages 21-22): Chamila Kappagoda, Indika Senavirathna, Thilini Agampodi, and Suneth Buddhika Agampodi. Role of toll-like receptor 2 during infection of leptospira spp: a systematic review. PLOS ONE, 19:e0312466, Dec 2024. URL: https://doi.org/10.1371/journal.pone.0312466, doi:10.1371/journal.pone.0312466. This article has 1 citations and is from a peer-reviewed journal.

{ }

Source YAML

click to show

name: Leptospirosis
creation_date: '2026-03-03T16:18:51Z'
updated_date: '2026-04-10T16:56:38Z'
category: Infectious
description: >-
  Leptospirosis is a zoonotic spirochetal infection caused by pathogenic
  Leptospira species, with clinical severity ranging from self-limited febrile
  illness to severe multi-organ dysfunction (including jaundice, pulmonary
  hemorrhage, and acute kidney injury).
disease_term:
  preferred_term: leptospirosis
  term:
    id: MONDO:0005825
    label: leptospirosis
classifications:
  harrisons_chapter:
  - classification_value: infectious disease
    evidence:
    - reference: PMID:29621837
      reference_title: "Leptospirosis: An important zoonosis acquired through work, play and travel."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "BACKGROUND: Leptospirosis is one of the most common zoonotic diseases worldwide."
      explanation: Supports classification as an infectious disease.
  - classification_value: bacterial infectious disease
    evidence:
    - reference: DOI:10.1128/spectrum.03135-22
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Leptospirosis is a zoonotic disease of global importance. It is caused by a Gram-negative bacterial spirochete of the genus"
      explanation: Supports bacterial infectious disease classification.
definitions:
- name: Clinical syndrome definition
  definition_type: CASE_DEFINITION
  description: >-
    Leptospirosis includes a broad clinical spectrum from asymptomatic or
    influenza-like illness to severe icteric and hemorrhagic multi-organ disease.
  scope: Clinical syndrome in human patients
  evidence:
  - reference: DOI:10.3390/kidneydial4020006
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance."
    explanation: Defines the broad severity range and hallmark severe manifestations.
- name: Practical diagnostic framework
  definition_type: DIAGNOSTIC_CRITERIA
  description: >-
    Clinical suspicion in exposed patients with acute febrile illness should be
    followed by laboratory confirmation using serology and/or PCR.
  scope: Frontline and hospital diagnostic workflow
  evidence:
  - reference: PMID:29621837
    reference_title: "Leptospirosis: An important zoonosis acquired through work, play and travel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with risk factors for leptospirosis, a high index of clinical suspicion is important to ensure early diagnosis and treatment."
    explanation: Supports risk-informed clinical suspicion as the diagnostic entry point.
  - reference: DOI:10.1371/journal.pntd.0012449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Enrollment was based on leptospirosis-compatible clinical syndrome and a positive preliminary serological test, with PCR used to confirm the disease."
    explanation: Supports serology plus PCR-confirmation workflow.
parents:
- zoonotic bacterial infection
- spirochetal infection
synonyms:
- Weil disease
- Weil syndrome
has_subtypes:
- name: Anicteric leptospirosis
  classification: clinical
  description: Self-limited influenza-like leptospirosis without classic severe icteric complications.
  evidence:
  - reference: PMID:28722888
    reference_title: "Leptospirosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Leptospirosis can cause a self-limiting influenza-like illness or a much more serious disease."
    explanation: Supports a milder, self-limited clinical subtype.
- name: Severe icteric leptospirosis (Weil disease)
  classification: clinical
  description: Severe leptospirosis with risk of multi-organ failure and death.
  evidence:
  - reference: PMID:28722888
    reference_title: "Leptospirosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This condition is known as Weil disease, and it can progress to multiorgan failure with the potential for death."
    explanation: Supports severe icteric leptospirosis as a distinct high-risk subtype.
- name: Severe pulmonary leptospirosis (ARDS-associated)
  classification: clinical
  description: Severe pulmonary leptospirosis can present with ARDS and require rescue extracorporeal support.
  evidence:
  - reference: DOI:10.3138/jammi-2023-0033
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Extracorporeal life support (ECLS) has been used as salvage therapy for severe leptospirosis complicated by acute respiratory distress syndrome (ARDS)."
    explanation: Supports a pulmonary-critical subtype characterized by ARDS in severe leptospirosis.
infectious_agent:
- name: Pathogenic Leptospira species
  infectious_agent_term:
    preferred_term: Leptospira
    term:
      id: NCBITaxon:171
      label: Leptospira
  description: Pathogenic spirochetes in the genus Leptospira cause human leptospirosis.
  evidence:
  - reference: DOI:10.1128/spectrum.03135-22
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Leptospirosis is a zoonotic disease of global importance. It is caused by a Gram-negative bacterial spirochete of the genus"
    explanation: Supports Leptospira genus as the causative infectious agent.
- name: Leptospira interrogans
  infectious_agent_term:
    preferred_term: Leptospira interrogans
    term:
      id: NCBITaxon:173
      label: Leptospira interrogans
  description: A major pathogenic Leptospira species used in contemporary virulence studies.
  evidence:
  - reference: DOI:10.3389/fmicb.2023.1199660
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In this work, we tailored plasmids for silencing the major proteins of L. interrogans serovar Copenhageni strain Fiocruz L1-130, namely LipL32, LipL41, LipL21 and OmpL1."
    explanation: Confirms L. interrogans as a key pathogenic species in mechanistic pathogenesis work.
transmission:
- name: Animal-contact zoonotic transmission
  description: Human infection occurs through contact with infected animals and their contaminated excreta.
  evidence:
  - reference: PMID:29621837
    reference_title: "Leptospirosis: An important zoonosis acquired through work, play and travel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infection occurs through contact with infected animals, or soil or water that has been contaminated by the urine of infected animals."
    explanation: Supports direct and indirect zoonotic transmission from infected animals.
- name: Waterborne and soil-associated transmission
  description: Infection is frequently acquired from urine-contaminated environmental water or soil.
  evidence:
  - reference: PMID:29621837
    reference_title: "Leptospirosis: An important zoonosis acquired through work, play and travel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infection occurs through contact with infected animals, or soil or water that has been contaminated by the urine of infected animals."
    explanation: Supports environmental water/soil as major transmission media.
- name: Exposure-risk amplification during floods and recreation
  description: Floodwaters and recreational/occupational exposures increase transmission risk.
  evidence:
  - reference: PMID:29621837
    reference_title: "Leptospirosis: An important zoonosis acquired through work, play and travel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Risk factors include occupational and recreational exposures, contact with floodwaters, and travel to areas with a high risk of leptospirosis, particularly tropical, developing countries."
    explanation: Supports flood-associated and activity-associated transmission risk contexts.
progression:
- phase: Early undifferentiated febrile illness
  notes: Initial illness can be non-specific and overlap with other febrile syndromes, delaying diagnosis.
  evidence:
  - reference: PMID:29621837
    reference_title: "Leptospirosis: An important zoonosis acquired through work, play and travel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leptospirosis is sometimes misdiagnosed because clinical presentation can be non-specific and overlap with many other causes of acute febrile illnesses."
    explanation: Supports an early non-specific febrile phase with diagnostic ambiguity.
- phase: Severe multi-organ dysfunction phase
  notes: A subset progresses to severe disease with jaundice, hemorrhage, meningitis, and acute kidney injury.
  evidence:
  - reference: DOI:10.3390/kidneydial4020006
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance."
    explanation: Supports progression from mild disease to severe multi-organ involvement.
- phase: Critical-care rescue phase
  notes: Patients with severe pulmonary and multi-organ failure may require extracorporeal rescue support.
  evidence:
  - reference: DOI:10.3138/jammi-2023-0033
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ECLS is a viable rescue strategy in severe leptospirosis, even with established MSOF."
    explanation: Supports advanced rescue interventions in late critical illness.
pathophysiology:
- name: VM protein-mediated epithelial barrier disruption
  description: Secreted virulence-modifying proteins exploit host calcium signaling to destabilize epithelial junctions and enable early barrier breach.
  cell_types:
  - preferred_term: epithelial cell
    term:
      id: CL:0000066
      label: epithelial cell
  biological_processes:
  - preferred_term: cell junction organization
    modifier: DYSREGULATED
    term:
      id: GO:0034330
      label: cell junction organization
  - preferred_term: tight junction disassembly
    modifier: INCREASED
    term:
      id: GO:1905071
      label: tight junction disassembly
  evidence:
  - reference: PMID:41634022
    reference_title: "In vivo dual RNA-Seq uncovers key effectors of epithelial barrier disruption by an extracellular pathogen."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We demonstrate that, upon infection, an increase in intracellular calcium triggers tight junction destabilization, by activating the calmodulin and myosin light chain kinase signalization."
    explanation: Supports a calcium-calmodulin-MLCK mechanism for early epithelial barrier disruption.
  - reference: PMID:41634022
    reference_title: "In vivo dual RNA-Seq uncovers key effectors of epithelial barrier disruption by an extracellular pathogen."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We identify two bacterial effectors of the Virulence-Modifying (VM) proteins family, structurally related to toxin-like proteins, that promote modulation of calcium homeostasis and disruption of cell-cell junctions, thereby allowing Leptospira translocation across epithelium barriers, tissue colonization and pathogenicity."
    explanation: Supports VM proteins as the leptospiral effectors that drive epithelial junctional disruption and barrier breach.
  downstream:
  - target: Barrier transcytosis across endothelial and epithelial monolayers
    description: Junction destabilization facilitates traversal of host cell barriers and early dissemination.
    evidence:
    - reference: PMID:41634022
      reference_title: "In vivo dual RNA-Seq uncovers key effectors of epithelial barrier disruption by an extracellular pathogen."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We identify two bacterial effectors of the Virulence-Modifying (VM) proteins family, structurally related to toxin-like proteins, that promote modulation of calcium homeostasis and disruption of cell-cell junctions, thereby allowing Leptospira translocation across epithelium barriers, tissue colonization and pathogenicity."
      explanation: Supports a direct link from VM protein-mediated junctional injury to leptospiral barrier traversal.
- name: ColA-mediated collagen degradation
  description: Pathogenic Leptospira expresses collagenase activity that degrades host collagen substrates during invasive infection.
  biological_processes:
  - preferred_term: collagen catabolic process
    modifier: INCREASED
    term:
      id: GO:0030574
      label: collagen catabolic process
  evidence:
  - reference: PMID:24277745
    reference_title: "Identification of collagenase as a critical virulence factor for invasiveness and transmission of pathogenic Leptospira species."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Recombinant or native ColA hydrolyzed all the tested substrates in which type III collagen was the favorite substrate with 2.16 mg/mL Km and 35.6 h(-)(1) Kcat values."
    explanation: Supports collagenase-mediated degradation of host collagen as a discrete invasive mechanism.
  downstream:
  - target: Barrier transcytosis across endothelial and epithelial monolayers
    description: Collagen degradation promotes traversal of host endothelial and epithelial barriers.
    evidence:
    - reference: PMID:24277745
      reference_title: "Identification of collagenase as a critical virulence factor for invasiveness and transmission of pathogenic Leptospira species."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Compared with wild-type strain, ΔcolA mutant displayed much-attenuated transcytosis through HEK293 and HUVEC monolayers"
      explanation: Supports a direct link between ColA activity and barrier transcytosis in host cell monolayers.
- name: Barrier transcytosis across endothelial and epithelial monolayers
  description: Pathogenic leptospires traverse endothelial and epithelial cell barriers during invasive infection.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  biological_processes:
  - preferred_term: transcytosis
    modifier: INCREASED
    term:
      id: GO:0045056
      label: transcytosis
  evidence:
  - reference: PMID:24277745
    reference_title: "Identification of collagenase as a critical virulence factor for invasiveness and transmission of pathogenic Leptospira species."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Compared with wild-type strain, ΔcolA mutant displayed much-attenuated transcytosis through HEK293 and HUVEC monolayers"
    explanation: Supports transcellular passage across epithelial and endothelial barriers as an invasive step.
  downstream:
  - target: Hematogenous leptospiral dissemination
    description: Efficient barrier crossing increases bloodstream and organ burden during infection.
    evidence:
    - reference: PMID:24277745
      reference_title: "Identification of collagenase as a critical virulence factor for invasiveness and transmission of pathogenic Leptospira species."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Compared with wild-type strain, ΔcolA mutant displayed much-attenuated transcytosis through HEK293 and HUVEC monolayers, and less leptospires in blood, lung, liver, kidney and urine and 25-fold-decreased 50% lethal dose and milder histopathological injury in hamsters."
      explanation: Hamster infection data support a downstream link from barrier traversal to higher blood and organ burdens.
- name: Hematogenous leptospiral dissemination
  description: Pathogenic Leptospira disseminate through blood during acute systemic infection.
  locations:
  - preferred_term: blood
    term:
      id: UBERON:0000178
      label: blood
  biological_processes:
  - preferred_term: response to molecule of bacterial origin
    modifier: INCREASED
    term:
      id: GO:0002237
      label: response to molecule of bacterial origin
  evidence:
  - reference: DOI:10.3390/kidneydial4020006
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance."
    explanation: Supports systemic spread associated with progression to severe disease.
  downstream:
  - target: TLR2 signaling activation in monocytes and macrophages
    description: Systemic infection is associated with activation of TLR2-linked innate sensing.
    evidence:
    - reference: DOI:10.1371/journal.pone.0312466
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "We assessed the direct TLR2 expression and indirect TLR2 involvement via the secretion/mRNA expression of immune effectors during leptospirosis."
      explanation: Supports linkage between disseminated infection and TLR2-centered innate signaling.
  - target: Leptospiral GLP engagement of Na/K-ATPase
    description: Circulating leptospiral endotoxin engages host Na/K-ATPase during systemic infection.
    evidence:
    - reference: DOI:10.3390/microorganisms11071695
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Na/K-ATPase is the molecular target of the leptospiral endotoxin (glycolipoprotein—GLP)."
      explanation: Supports a mechanistic link from systemic infection to Na/K-ATPase targeting.
  - target: cGAS-STING-dependent type I interferon response
    description: Cytosolic DNA sensing in macrophages activates a host-defense interferon program during systemic infection.
    evidence:
    - reference: PMID:41499635
      reference_title: "cGAS-STING dependent type I IFN reduces Leptospira interrogans renal colonization in mice."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We show that L. interrogans induces a robust type I interferon (IFN) response in human and murine macrophages that is dependent on the cytosolic dsDNA sensor Cyclic GMP-AMP Synthase (cGAS) and the Stimulator of IFN Genes (STING) signaling pathway."
      explanation: Supports activation of cGAS-STING-dependent type I interferon signaling as a host response to disseminated leptospiral infection.
- name: cGAS-STING-dependent type I interferon response
  description: Cytosolic DNA sensing in macrophages triggers cGAS-STING signaling that helps restrain renal colonization during leptospiral infection.
  genes:
  - preferred_term: MB21D1
    term:
      id: hgnc:29816
      label: MB21D1
  - preferred_term: STING1
    term:
      id: hgnc:27962
      label: STING1
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: cGAS-STING signaling pathway
    modifier: INCREASED
    term:
      id: GO:0140896
      label: cGAS/STING signaling pathway
  evidence:
  - reference: PMID:41499635
    reference_title: "cGAS-STING dependent type I IFN reduces Leptospira interrogans renal colonization in mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that L. interrogans induces a robust type I interferon (IFN) response in human and murine macrophages that is dependent on the cytosolic dsDNA sensor Cyclic GMP-AMP Synthase (cGAS) and the Stimulator of IFN Genes (STING) signaling pathway."
    explanation: Supports cGAS-STING-dependent interferon signaling in infected macrophages as a discrete mechanistic response.
  - reference: PMID:41499635
    reference_title: "cGAS-STING dependent type I IFN reduces Leptospira interrogans renal colonization in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Further, we show that mice deficient in the IFNα/β receptor subunit 1 (IFNAR1) or STING had higher bacterial burdens and increased renal colonization following infection in vivo suggesting that cGAS-STING-driven type I IFN is required for the host defense against L. interrogans."
    explanation: Mouse infection data support this pathway as a host-defense mechanism that limits renal colonization.
- name: TLR2 signaling activation in monocytes and macrophages
  description: TLR2-dependent innate signaling is activated in myeloid cells during leptospirosis.
  genes:
  - preferred_term: TLR2
    term:
      id: hgnc:11848
      label: TLR2
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: toll-like receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0002224
      label: toll-like receptor signaling pathway
  evidence:
  - reference: DOI:10.1371/journal.pone.0312466
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We assessed the direct TLR2 expression and indirect TLR2 involvement via the secretion/mRNA expression of immune effectors during leptospirosis."
    explanation: Supports activation of a TLR2-centered innate signaling node.
  - reference: DOI:10.1371/journal.pone.0312466
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "Even though increased TLR2 expression in in-vivo and in-vitro studies was evident, human studies reported mixed results showing that the postulated effect of TLR2 response based on other studies may not be valid for human leptospirosis."
    explanation: Captures uncertainty in direct translation of model-system TLR2 findings to human disease.
  downstream:
  - target: Cytokine and chemokine upregulation
    description: TLR2-linked signaling drives increased cytokine and chemokine programs.
    evidence:
    - reference: DOI:10.1371/journal.pone.0312466
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Notably, we observed the secretion/mRNA expression of several cytokines (IL6, IL8, IL-1β, TNFα, IFNγ, IL10, CCL2/MCP-1, CCL10, COX2, CXCL1/KC, CXCL2/MIP2) and immune effectors (hBD2, iNOS, Fibronectin, Oxygen, and Nitrogen reactive species) as key aspects of host TLR2 responses during leptospirosis."
      explanation: Supports transition from TLR2 signaling to broad inflammatory mediator upregulation.
- name: Cytokine and chemokine upregulation
  description: Pro-inflammatory cytokine and chemokine expression increases during acute leptospirosis.
  genes:
  - preferred_term: CCL2
    term:
      id: hgnc:10618
      label: CCL2
  - preferred_term: IL1B
    term:
      id: hgnc:5992
      label: IL1B
  biological_processes:
  - preferred_term: positive regulation of cytokine production
    modifier: INCREASED
    term:
      id: GO:0001819
      label: positive regulation of cytokine production
  evidence:
  - reference: DOI:10.1371/journal.pone.0312466
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Notably, we observed the secretion/mRNA expression of several cytokines (IL6, IL8, IL-1β, TNFα, IFNγ, IL10, CCL2/MCP-1, CCL10, COX2, CXCL1/KC, CXCL2/MIP2) and immune effectors (hBD2, iNOS, Fibronectin, Oxygen, and Nitrogen reactive species) as key aspects of host TLR2 responses during leptospirosis."
    explanation: Supports increased inflammatory mediator output as a distinct event.
  downstream:
  - target: NLRP3 inflammasome complex assembly
    description: Cytokine-rich innate activation is associated with inflammasome pathway engagement.
    evidence:
    - reference: DOI:10.3390/microorganisms11071695
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Synergistically, multiple molecular stimuli are prompted during the infection, activating inflammasomes and Na/K-ATPase signalosome, leading to pro-inflammatory and metabolic alterations during leptospirosis."
      explanation: Supports transition from broad inflammatory activation to inflammasome assembly.
- name: NLRP3 inflammasome complex assembly
  description: Leptospirosis-associated molecular stimuli activate NLRP3 inflammasome assembly.
  genes:
  - preferred_term: NLRP3
    term:
      id: hgnc:16400
      label: NLRP3
  - preferred_term: CASP1
    term:
      id: hgnc:1499
      label: CASP1
  biological_processes:
  - preferred_term: NLRP3 inflammasome complex assembly
    modifier: INCREASED
    term:
      id: GO:0044546
      label: NLRP3 inflammasome complex assembly
  evidence:
  - reference: DOI:10.3390/microorganisms11071695
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Synergistically, multiple molecular stimuli are prompted during the infection, activating inflammasomes and Na/K-ATPase signalosome, leading to pro-inflammatory and metabolic alterations during leptospirosis."
    explanation: Supports activation of the inflammasome node as a separate mechanistic event.
  downstream:
  - target: Increased interleukin-1 beta production
    description: Inflammasome activation promotes IL-1beta production as a downstream inflammatory step.
    evidence:
    - reference: DOI:10.1371/journal.pone.0312466
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Notably, we observed the secretion/mRNA expression of several cytokines (IL6, IL8, IL-1β, TNFα, IFNγ, IL10, CCL2/MCP-1, CCL10, COX2, CXCL1/KC, CXCL2/MIP2) and immune effectors (hBD2, iNOS, Fibronectin, Oxygen, and Nitrogen reactive species) as key aspects of host TLR2 responses during leptospirosis."
      explanation: Supports IL-1beta as a downstream pro-inflammatory output in the innate cascade.
- name: Increased interleukin-1 beta production
  description: Interleukin-1 beta production increases during innate immune activation in leptospirosis.
  genes:
  - preferred_term: IL1B
    term:
      id: hgnc:5992
      label: IL1B
  biological_processes:
  - preferred_term: interleukin-1 beta production
    modifier: INCREASED
    term:
      id: GO:0032611
      label: interleukin-1 beta production
  evidence:
  - reference: DOI:10.1371/journal.pone.0312466
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Notably, we observed the secretion/mRNA expression of several cytokines (IL6, IL8, IL-1β, TNFα, IFNγ, IL10, CCL2/MCP-1, CCL10, COX2, CXCL1/KC, CXCL2/MIP2) and immune effectors (hBD2, iNOS, Fibronectin, Oxygen, and Nitrogen reactive species) as key aspects of host TLR2 responses during leptospirosis."
    explanation: Supports increased IL-1beta production as a discrete inflammatory event.
  downstream:
  - target: Fever
    description: Increased IL-1beta and systemic inflammatory signaling contribute to fever.
    evidence:
    - reference: DOI:10.1371/journal.pntd.0012449
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Leptospirosis is responsible for various clinical syndromes, classically linked with fever and acute kidney injury."
      explanation: Supports linkage between inflammatory pathway activation and febrile phenotype.
  - target: Headache
    description: Systemic inflammatory mediator elevation contributes to common constitutional headache.
    evidence:
    - reference: DOI:10.1371/journal.pntd.0012449
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The most frequent symptoms in patients with a positive PCR test were headache (91.9%; 34/37), chills and sweating (80.6%; 29/37), nausea (75%; 27/37), dizziness (74.3%; 26/37), vomiting (61.1%; 22/37), congestion (56.8%; 21/37), and conjunctival suffusion (51.4%; 19/37)."
      explanation: Supports a downstream link from inflammatory cytokine programs to headache prevalence.
- name: TolC-mediated factor H recruitment
  description: Leptospiral TolC interacts with factor H and preserves factor H cofactor activity.
  notes: Current support for this TolC-centered immune-evasion mechanism is derived from in vitro experiments rather than direct in vivo infection models.
  evidence:
  - reference: DOI:10.1128/iai.00419-24
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional assays demonstrated that rTolC-bound FH retained cofactor activity for C3b cleavage, highlighting TolC’s role in complement regulation."
    explanation: Supports a specific complement-regulatory interaction mediated by TolC.
  downstream:
  - target: Reduced membrane attack complex deposition
    description: Factor H-assisted complement control via TolC reduces terminal complement activity.
    evidence:
    - reference: DOI:10.1128/iai.00419-24
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The rTolC protein inhibited both the alternative and the classical pathway-mediated membrane attack complex (MAC) deposition in vitro."
      explanation: Supports a direct downstream effect on MAC deposition.
- name: Reduced membrane attack complex deposition
  description: Complement terminal pathway activity is reduced by TolC-dependent immune evasion.
  biological_processes:
  - preferred_term: complement activation
    modifier: DECREASED
    term:
      id: GO:0006956
      label: complement activation
  evidence:
  - reference: DOI:10.1128/iai.00419-24
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The rTolC protein inhibited both the alternative and the classical pathway-mediated membrane attack complex (MAC) deposition in vitro."
    explanation: Supports reduced complement terminal pathway activity as a discrete mechanism.
  downstream:
  - target: Persistent tissue colonization by Leptospira
    description: Reduced complement-mediated killing supports persistence in host tissues.
    evidence:
    - reference: DOI:10.1128/iai.00419-24
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These findings indicate that TolC contributes to leptospiral virulence by promoting host tissue colonization and evading the immune response, presenting it as a potential target for diagnostic and therapeutic strategies."
      explanation: Supports complement-evasion-driven colonization persistence.
- name: Persistent tissue colonization by Leptospira
  description: In vitro evidence supports a model in which immune evasion promotes ongoing leptospiral tissue colonization and virulence.
  notes: Persistent colonization in this TolC-driven chain is currently inferred from in vitro immune-evasion assays rather than directly demonstrated in human or animal infection models.
  evidence:
  - reference: DOI:10.1128/iai.00419-24
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These findings indicate that TolC contributes to leptospiral virulence by promoting host tissue colonization and evading the immune response, presenting it as a potential target for diagnostic and therapeutic strategies."
    explanation: Supports persistent colonization as a separate virulence step.
  downstream:
  - target: Hematogenous leptospiral dissemination
    description: Persistent colonization enables continuing systemic dissemination.
    evidence:
    - reference: DOI:10.1128/iai.00419-24
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These findings indicate that TolC contributes to leptospiral virulence by promoting host tissue colonization and evading the immune response, presenting it as a potential target for diagnostic and therapeutic strategies."
      explanation: Supports reinjection of persistent infection into systemic disease progression.
- name: Leptospiral GLP engagement of Na/K-ATPase
  description: Leptospiral glycolipoprotein directly targets host Na/K-ATPase.
  biological_processes:
  - preferred_term: response to lipopolysaccharide
    modifier: INCREASED
    term:
      id: GO:0032496
      label: response to lipopolysaccharide
  evidence:
  - reference: DOI:10.3390/microorganisms11071695
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Na/K-ATPase is the molecular target of the leptospiral endotoxin (glycolipoprotein—GLP)."
    explanation: Supports direct molecular targeting of Na/K-ATPase by leptospiral GLP.
  downstream:
  - target: Na/K-ATPase dysfunction in endothelial and kidney epithelial cells
    description: Direct GLP-Na/K-ATPase interaction impairs pump function across vulnerable host cell types.
    evidence:
    - reference: DOI:10.3390/microorganisms11071695
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Na/K-ATPase dysfunctions on different types of cells give rise to the organ disorders manifested in leptospirosis."
      explanation: Supports transition from direct target engagement to cellular dysfunction.
- name: Na/K-ATPase dysfunction in endothelial and kidney epithelial cells
  description: Na/K-ATPase dysfunction in vascular and renal cells drives inflammatory-metabolic dysregulation.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  biological_processes:
  - preferred_term: inflammatory response
    modifier: DYSREGULATED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: DOI:10.3390/microorganisms11071695
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Na/K-ATPase dysfunctions on different types of cells give rise to the organ disorders manifested in leptospirosis."
    explanation: Supports cellular dysfunction as a mechanistic bridge to organ-level injury.
  - reference: DOI:10.3390/microorganisms11071695
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Synergistically, multiple molecular stimuli are prompted during the infection, activating inflammasomes and Na/K-ATPase signalosome, leading to pro-inflammatory and metabolic alterations during leptospirosis."
    explanation: Supports inflammatory-metabolic dysregulation downstream of Na/K-ATPase perturbation.
  downstream:
  - target: Multi-organ tissue injury in severe leptospirosis
    description: Cell-level Na/K-ATPase dysfunction propagates to tissue-level organ injury.
    evidence:
    - reference: DOI:10.3390/kidneydial4020006
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance."
      explanation: Supports translation of cellular dysfunction into multi-organ clinical injury.
- name: VE-cadherin adherens junction disruption in endothelial cells
  description: Virulent leptospires disrupt endothelial VE-cadherin localization in adherens junctions, linking host-cell association to vascular barrier injury.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: adherens junction organization
    modifier: DECREASED
    term:
      id: GO:0034332
      label: adherens junction organization
  evidence:
  - reference: PMID:41592120
    reference_title: "In vitro and in vivo endothelial interactions of Leptospira species are markers of virulence."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Additionally, bacterial association with host cells correlates with the loss of VE-cadherin localization in adherens junctions."
    explanation: Supports endothelial adherens junction disruption as a consequence of leptospiral interaction with host cells.
  - reference: PMID:41592120
    reference_title: "In vitro and in vivo endothelial interactions of Leptospira species are markers of virulence."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our findings indicate that VE-cadherin disruption correlates with P1 + species and the presence of virulence-associated genes."
    explanation: Supports a link between endothelial junction injury and higher-virulence pathogenic leptospires.
  downstream:
  - target: Pulmonary microvascular damage in hemorrhagic leptospirosis
    description: Endothelial adherens junction loss contributes to vascular leakage and downstream pulmonary microvascular injury.
    evidence:
    - reference: PMID:41592120
      reference_title: "In vitro and in vivo endothelial interactions of Leptospira species are markers of virulence."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Additionally, bacterial association with host cells correlates with the loss of VE-cadherin localization in adherens junctions."
      explanation: Supports endothelial barrier injury as an upstream event feeding into severe vascular and pulmonary pathology.
- name: Pulmonary microvascular damage in hemorrhagic leptospirosis
  description: Hemorrhagic leptospirosis is associated with prominent injury to the lung microcirculation.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  evidence:
  - reference: PMID:23951234
    reference_title: "Human hemorrhagic pulmonary leptospirosis: pathological findings and pathophysiological correlations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prominent vascular damage was present in the lung microcirculation, with decreased CD34 and preserved aquaporin 1 expression."
    explanation: Human necropsy data directly support pulmonary microvascular injury as a distinct pathophysiological lesion.
  downstream:
  - target: Pulmonary hemorrhage
    description: Lung microvascular injury promotes alveolar edema and hemorrhage.
    evidence:
    - reference: PMID:23951234
      reference_title: "Human hemorrhagic pulmonary leptospirosis: pathological findings and pathophysiological correlations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "At the periphery and even inside the extensive areas of edema and intraalveolar hemorrhage, enlarged, apparently hypertrophic type I pneumocytes (PI) were detected"
      explanation: Supports a direct link between pulmonary vascular injury and intraalveolar hemorrhage in human disease.
- name: Multi-organ tissue injury in severe leptospirosis
  description: Severe leptospirosis causes clinically significant injury across kidney, liver, and lung.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: inflammatory response
    modifier: DYSREGULATED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: DOI:10.3390/kidneydial4020006
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance."
    explanation: Supports severe disease as a distinct multi-organ injury stage.
  - reference: PMID:17044471
    reference_title: "Alleviation of renal and pulmonary injury by immunomodulation in leptospirosis: hamster model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The autopsy findings revealed severe interstitial nephritis and severe pulmonary hemorrhage."
    explanation: Hamster model evidence independently recapitulates combined renal and pulmonary tissue injury in severe leptospirosis.
  downstream:
  - target: Acute kidney injury
    description: Kidney involvement manifests as acute kidney injury in severe disease.
    evidence:
    - reference: DOI:10.3390/kidneydial4020006
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance."
      explanation: Supports acute kidney injury as a direct clinical consequence of multi-organ injury.
  - target: Jaundice
    description: Liver involvement manifests clinically as jaundice.
    evidence:
    - reference: DOI:10.3390/kidneydial4020006
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance."
      explanation: Supports jaundice as a direct clinical consequence of multi-organ injury.
  - target: Pulmonary hemorrhage
    description: Severe lung and vascular injury can culminate in pulmonary hemorrhage.
    evidence:
    - reference: PMID:29621837
      reference_title: "Leptospirosis: An important zoonosis acquired through work, play and travel."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Delays in treatment could increase the risk of severe complications, including pulmonary haemorrhage, acute renal failure and acute liver failure."
      explanation: Supports pulmonary hemorrhage as a severe downstream consequence.
  - target: Coagulation derangement in critical leptospirosis
    description: Critical multi-organ injury can be accompanied by systemic coagulation derangement.
    evidence:
    - reference: DOI:10.3138/jammi-2023-0033
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Additional complications included diffuse intravascular coagulation, necrotizing pancreatitis, and limb ischemia."
      explanation: Supports downstream coagulation-pathway complications in severe disease.
- name: Coagulation derangement in critical leptospirosis
  description: Severe leptospirosis can involve dysregulated coagulation with disseminated intravascular coagulation.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: blood coagulation
    modifier: DYSREGULATED
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: DOI:10.3138/jammi-2023-0033
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional complications included diffuse intravascular coagulation, necrotizing pancreatitis, and limb ischemia."
    explanation: Supports a distinct coagulopathy mechanism in critical leptospirosis.
  downstream:
  - target: Disseminated intravascular coagulation
    description: Coagulation derangement manifests clinically as disseminated intravascular coagulation.
    evidence:
    - reference: DOI:10.3138/jammi-2023-0033
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Additional complications included diffuse intravascular coagulation, necrotizing pancreatitis, and limb ischemia."
      explanation: Supports the clinical DIC phenotype as a direct downstream outcome of severe coagulopathy.
phenotypes:
- name: Fever
  category: Constitutional
  frequency: VERY_FREQUENT
  description: Fever is a common presenting feature of acute leptospirosis.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: DOI:10.1371/journal.pntd.0012449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leptospirosis is responsible for various clinical syndromes, classically linked with fever and acute kidney injury."
    explanation: Supports fever as a core clinical phenotype.
- name: Headache
  category: Neurological
  frequency: VERY_FREQUENT
  description: Headache is among the most frequent symptoms in PCR-confirmed acute leptospirosis.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: DOI:10.1371/journal.pntd.0012449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent symptoms in patients with a positive PCR test were headache (91.9%; 34/37), chills and sweating (80.6%; 29/37), nausea (75%; 27/37), dizziness (74.3%; 26/37), vomiting (61.1%; 22/37), congestion (56.8%; 21/37), and conjunctival suffusion (51.4%; 19/37)."
    explanation: Supports very high headache frequency in confirmed cases.
- name: Myalgia
  category: Constitutional
  frequency: FREQUENT
  description: Myalgia is a common and diagnostically important symptom in acute leptospirosis, often prominent in the calf muscles.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:24450239
    reference_title: "Clinical profile of patients diagnosed with leptospirosis after a typhoon: a multicenter study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other findings were myalgia (78.1%), malaise (74.9%), conjunctival suffusion (59.3%), oliguria (56.6%), diarrhea (39%), and jaundice (38%)."
    explanation: Supports myalgia as a frequent human clinical manifestation in confirmed leptospirosis.
- name: Chills
  category: Constitutional
  frequency: FREQUENT
  description: Chills are common during acute febrile presentations of confirmed leptospirosis.
  phenotype_term:
    preferred_term: Chills
    term:
      id: HP:0025143
      label: Chills
  evidence:
  - reference: DOI:10.1371/journal.pntd.0012449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent symptoms in patients with a positive PCR test were headache (91.9%; 34/37), chills and sweating (80.6%; 29/37), nausea (75%; 27/37), dizziness (74.3%; 26/37), vomiting (61.1%; 22/37), congestion (56.8%; 21/37), and conjunctival suffusion (51.4%; 19/37)."
    explanation: Supports chills as a frequent constitutional symptom in PCR-confirmed acute disease.
- name: Nausea
  category: Gastrointestinal
  frequency: FREQUENT
  description: Nausea occurs in most symptomatic confirmed cases.
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
  evidence:
  - reference: DOI:10.1371/journal.pntd.0012449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent symptoms in patients with a positive PCR test were headache (91.9%; 34/37), chills and sweating (80.6%; 29/37), nausea (75%; 27/37), dizziness (74.3%; 26/37), vomiting (61.1%; 22/37), congestion (56.8%; 21/37), and conjunctival suffusion (51.4%; 19/37)."
    explanation: Supports frequent nausea in laboratory-confirmed disease.
- name: Vomiting
  category: Gastrointestinal
  frequency: FREQUENT
  description: Vomiting is common in acute confirmed leptospirosis.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: DOI:10.1371/journal.pntd.0012449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent symptoms in patients with a positive PCR test were headache (91.9%; 34/37), chills and sweating (80.6%; 29/37), nausea (75%; 27/37), dizziness (74.3%; 26/37), vomiting (61.1%; 22/37), congestion (56.8%; 21/37), and conjunctival suffusion (51.4%; 19/37)."
    explanation: Supports vomiting as a frequent acute phenotype.
- name: Conjunctival suffusion
  category: Ophthalmologic
  frequency: FREQUENT
  description: Conjunctival suffusion/conjunctival inflammation is a frequent sign in confirmed cases.
  notes: HPO did not yield a precise conjunctival suffusion term in the local ontology build. HP:0000509 (Conjunctivitis) is retained as the closest available conjunctival abnormality mapping, but conjunctival suffusion is clinically distinct because it classically lacks purulent discharge.
  phenotype_term:
    preferred_term: Conjunctival suffusion
    term:
      id: HP:0000509
      label: Conjunctivitis
  evidence:
  - reference: DOI:10.1371/journal.pntd.0012449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent symptoms in patients with a positive PCR test were headache (91.9%; 34/37), chills and sweating (80.6%; 29/37), nausea (75%; 27/37), dizziness (74.3%; 26/37), vomiting (61.1%; 22/37), congestion (56.8%; 21/37), and conjunctival suffusion (51.4%; 19/37)."
    explanation: Supports conjunctival suffusion as a recurrent ocular sign.
- name: Jaundice
  category: Hepatic
  frequency: OCCASIONAL
  description: Jaundice is more characteristic of severe disease but not frequent in all confirmed febrile presentations.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: DOI:10.1371/journal.pntd.0012449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequency of clinical signs classically described in leptospirosis was low: jaundice (8.3%; 3/36) and anuria/oliguria (21.6%; 8/37)."
    explanation: Supports lower frequency of jaundice in this prospective confirmed cohort.
  - reference: DOI:10.3390/kidneydial4020006
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance."
    explanation: Confirms jaundice as part of severe multi-organ leptospirosis.
- name: Acute kidney injury
  category: Renal
  frequency: OCCASIONAL
  description: Renal injury is a classic and clinically important complication, especially in severe disease.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: DOI:10.1371/journal.pntd.0012449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leptospirosis is responsible for various clinical syndromes, classically linked with fever and acute kidney injury."
    explanation: Supports AKI as a core disease-linked complication.
  - reference: DOI:10.3390/kidneydial4020006
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance."
    explanation: Supports AKI as a major component of severe disease requiring intensive support.
- name: Oliguria
  category: Renal
  frequency: OCCASIONAL
  description: Oliguria/anuria occurs in a subset of confirmed cases and aligns with renal involvement.
  phenotype_term:
    preferred_term: Oliguria
    term:
      id: HP:0100520
      label: Oliguria
  evidence:
  - reference: DOI:10.1371/journal.pntd.0012449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequency of clinical signs classically described in leptospirosis was low: jaundice (8.3%; 3/36) and anuria/oliguria (21.6%; 8/37)."
    explanation: Supports oliguria/anuria as an occasional renal manifestation.
- name: Pulmonary hemorrhage
  category: Respiratory
  frequency: OCCASIONAL
  description: Pulmonary hemorrhage is a severe complication linked to delayed diagnosis and high-risk disease.
  phenotype_term:
    preferred_term: Pulmonary hemorrhage
    term:
      id: HP:0040223
      label: Pulmonary hemorrhage
  evidence:
  - reference: PMID:29621837
    reference_title: "Leptospirosis: An important zoonosis acquired through work, play and travel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Delays in treatment could increase the risk of severe complications, including pulmonary haemorrhage, acute renal failure and acute liver failure."
    explanation: Supports pulmonary hemorrhage as a severe leptospirosis complication.
  - reference: DOI:10.1371/journal.pntd.0012449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of complications was 21.6% (8/37), with pulmonary complications being the most frequent (75.0% 6/8)."
    explanation: Supports the prominence of pulmonary complications within complicated cases.
- name: Acute respiratory distress syndrome
  category: Respiratory
  frequency: OCCASIONAL
  description: Severe pulmonary leptospirosis can progress to ARDS requiring rescue support.
  phenotype_term:
    preferred_term: Acute respiratory distress syndrome
    term:
      id: HP:0033677
      label: Acute respiratory distress syndrome
  evidence:
  - reference: DOI:10.3138/jammi-2023-0033
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Extracorporeal life support (ECLS) has been used as salvage therapy for severe leptospirosis complicated by acute respiratory distress syndrome (ARDS)."
    explanation: Supports ARDS as a major severe pulmonary phenotype.
- name: Meningitis
  category: Neurological
  frequency: OCCASIONAL
  description: Meningitis can occur as part of severe multi-organ leptospirosis.
  phenotype_term:
    preferred_term: Meningitis
    term:
      id: HP:0001287
      label: Meningitis
  evidence:
  - reference: DOI:10.3390/kidneydial4020006
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spectrum of symptoms is variable and usually ranges from asymptomatic cases to severe manifestations involving multiple organ dysfunction accompanied by jaundice, hemorrhage, meningitis, and acute kidney injury that requires the need for intensive care assistance."
    explanation: Supports meningitis as a recognized severe manifestation.
- name: Disseminated intravascular coagulation
  category: Hematologic
  frequency: RARE
  description: Diffuse intravascular coagulation is reported among complications in critical severe leptospirosis.
  phenotype_term:
    preferred_term: Disseminated intravascular coagulation
    term:
      id: HP:0005521
      label: Disseminated intravascular coagulation
  evidence:
  - reference: DOI:10.3138/jammi-2023-0033
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional complications included diffuse intravascular coagulation, necrotizing pancreatitis, and limb ischemia."
    explanation: Supports DIC as a severe hematologic complication in reported critical cases.
- name: Thrombocytopenia
  category: Hematologic
  frequency: OCCASIONAL
  description: Thrombocytopenia is reported among severe manifestations in acute human leptospirosis cohorts.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: clinicaltrials:NCT05413720
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The research hypothesis is based on a suspected strong involvement of the immune system in the genesis of serious manifestations of the disease (hepatitis, renal failure, thrombocytopenia, intra-alveolar hemorrhage)."
    explanation: Supports thrombocytopenia as a severe clinical manifestation in human leptospirosis-focused cohorts.
diagnosis:
- name: Exposure-informed clinical evaluation
  description: Exposure history plus non-specific acute febrile presentation should trigger suspicion and testing.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
    qualifiers:
    - predicate:
        preferred_term: diagnostic procedure
        term:
          id: NCIT:C18020
          label: Diagnostic Procedure
      value:
        preferred_term: clinical evaluation
        term:
          id: NCIT:C124351
          label: Clinical Evaluation
  evidence:
  - reference: PMID:29621837
    reference_title: "Leptospirosis: An important zoonosis acquired through work, play and travel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with risk factors for leptospirosis, a high index of clinical suspicion is important to ensure early diagnosis and treatment."
    explanation: Supports risk-informed bedside assessment for diagnostic triage.
  - reference: PMID:35469592
    reference_title: "Fever in the Returning Traveler."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The differential diagnosis can be narrowed by thorough history-taking with particular attention to the patient's travel route, combined with a good knowledge of the geographic spread and incubation times of the main tropical diseases."
    explanation: Supports structured exposure/travel history-taking as a key diagnostic triage step for tropical febrile syndromes that include leptospirosis.
- name: Preliminary serologic screening
  description: Initial laboratory workups often include serologic testing before confirmatory molecular testing.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  evidence:
  - reference: DOI:10.1371/journal.pntd.0012449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Enrollment was based on leptospirosis-compatible clinical syndrome and a positive preliminary serological test, with PCR used to confirm the disease."
    explanation: Supports practical use of preliminary serology in clinical workflows.
- name: PCR-based confirmation
  description: PCR provides confirmatory evidence of acute leptospirosis in clinically suspected cases.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
    qualifiers:
    - predicate:
        preferred_term: diagnostic procedure
        term:
          id: NCIT:C18020
          label: Diagnostic Procedure
      value:
        preferred_term: polymerase chain reaction
        term:
          id: NCIT:C17003
          label: Polymerase Chain Reaction
  evidence:
  - reference: DOI:10.1371/journal.pntd.0012449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Enrollment was based on leptospirosis-compatible clinical syndrome and a positive preliminary serological test, with PCR used to confirm the disease."
    explanation: Supports PCR as a confirmatory diagnostic modality.
treatments:
- name: Antibiotic pharmacotherapy
  description: Antibiotics are central treatment across mild and severe presentations, with early therapy improving outcomes.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic procedure
        term:
          id: NCIT:C49236
          label: Therapeutic Procedure
      value:
        preferred_term: oral route of administration
        term:
          id: NCIT:C38288
          label: Oral Route of Administration
    - predicate:
        preferred_term: therapeutic procedure
        term:
          id: NCIT:C49236
          label: Therapeutic Procedure
      value:
        preferred_term: intravenous route of administration
        term:
          id: NCIT:C38276
          label: Intravenous Route of Administration
    - predicate:
        preferred_term: specify therapeutic agent
        term:
          id: NCIT:C157096
          label: Specify Therapeutic Agent
      value:
        preferred_term: antibiotic
        term:
          id: NCIT:C258
          label: Antibiotic
    therapeutic_agent:
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
    - preferred_term: ceftriaxone
      term:
        id: CHEBI:29007
        label: ceftriaxone
    - preferred_term: benzylpenicillin
      term:
        id: CHEBI:18208
        label: benzylpenicillin
  evidence:
  - reference: DOI:10.3389/fmicb.2024.1403765
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Emphasis is placed on antibiotic therapy, including recommendations for mild and severe cases, as well as the role of probiotics in modulating the gut microbiota."
    explanation: Supports antibiotics as first-line treatment across clinical severities.
  - reference: DOI:10.3390/kidneydial4020006
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although early antibiotic treatment is usually effective, in severe cases, it may require renal replacement therapy, invasive mechanical ventilation, vasoactive support, and invasive hemodynamic monitoring, increasing the risk of death."
    explanation: Supports benefit of early antibiotics and escalation needs in severe disease.
- name: Intensive supportive care for severe leptospirosis
  description: Severe disease may require multi-organ support including renal replacement therapy and mechanical ventilation.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: DOI:10.3390/kidneydial4020006
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although early antibiotic treatment is usually effective, in severe cases, it may require renal replacement therapy, invasive mechanical ventilation, vasoactive support, and invasive hemodynamic monitoring, increasing the risk of death."
    explanation: Supports ICU-level supportive interventions in severe leptospirosis.
- name: Adjunctive corticosteroid therapy (uncertain benefit)
  description: Corticosteroids may help selected severe pulmonary presentations, but current evidence remains inconclusive.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: DOI:10.3390/jcm13154310
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Although some studies suggest potential benefits, particularly for pulmonary complications, the evidence remains inconclusive due to the limited number of studies and their methodological limitations."
    explanation: Supports only partial confidence for routine corticosteroid use.
- name: Extracorporeal life support rescue
  description: ECLS/ECMO can be considered as rescue support in severe ARDS and multi-organ failure.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: DOI:10.3138/jammi-2023-0033
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ECLS is a viable rescue strategy in severe leptospirosis, even with established MSOF."
    explanation: Supports rescue ECLS in selected critically ill patients.
- name: Butyrate adjunctive strategy (preclinical)
  description: Experimental butyrate supplementation improved outcomes in hamster acute leptospirosis models via macrophage ROS-linked killing.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
    therapeutic_agent:
    - preferred_term: butyrate
      term:
        id: CHEBI:17968
        label: butyrate
  evidence:
  - reference: DOI:10.1128/mbio.01906-24
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "The depletion of SCFAs by antibiotic cocktail treatment reduced survival time after Leptospira infection while supplementation with butyrate but not acetate or propionate significantly amelioration of leptospirosis."
    explanation: Supports model-organism evidence for a host-directed adjunctive approach that is not yet validated for standard human care.
- name: Recombinant vaccine strategy development (investigational prevention)
  description: Recombinant vaccine approaches are under active development but face translational barriers before broad protective use.
  treatment_term:
    preferred_term: vaccination
    term:
      id: MAXO:0001017
      label: vaccination
  evidence:
  - reference: DOI:10.3390/pathogens12060787
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "However, developing recombinant vaccines for leptospirosis faces various challenges, including selecting the ideal expression platform or delivery system, assessing immunogenicity, selecting adjuvants, establishing vaccine formulation, demonstrating protective efficacy against lethal disease in homologous challenge, achieving full renal clearance using experimental models, and reproducibility of protective efficacy against heterologous challenge."
    explanation: Supports current investigational status of recombinant vaccine strategies and their unresolved translational constraints.
clinical_trials:
- name: NCT07127718
  phase: PHASE_II
  status: RECRUITING
  description: >-
    DeLEPTO Project 1 is a phase II trial evaluating CFI-guided risk
    stratification and adjunctive rescue strategies (plasma transfusion,
    hemoperfusion, ECMO) for complications of leptospirosis.
  target_phenotypes:
  - preferred_term: Pulmonary hemorrhage
    term:
      id: HP:0040223
      label: Pulmonary hemorrhage
  evidence:
  - reference: clinicaltrials:NCT07127718
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The goal of this clinical trial is to learn if complement factor I (CFI) works to predict development of complications in participants with leptospirosis."
    explanation: Supports an actively recruiting interventional trial focused on complication prediction and management in leptospirosis.
- name: NCT05413720
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    IMMUNOLEPTO is a completed mechanistic clinical study characterizing innate
    immune cell and cytokine profiles in acute human leptospirosis.
  target_phenotypes:
  - preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  - preferred_term: Pulmonary hemorrhage
    term:
      id: HP:0040223
      label: Pulmonary hemorrhage
  evidence:
  - reference: clinicaltrials:NCT05413720
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The research hypothesis is based on a suspected strong involvement of the immune system in the genesis of serious manifestations of the disease (hepatitis, renal failure, thrombocytopenia, intra-alveolar hemorrhage)."
    explanation: Supports a completed trial directly interrogating immune drivers of severe leptospirosis manifestations.
- name: NCT04034550
  phase: NOT_APPLICABLE
  status: ACTIVE_NOT_RECRUITING
  description: >-
    COLEPT is a prospective hospital-based cohort with one-year follow-up for
    clinical, bacteriological, and immunological characterization of acute
    leptospirosis.
  target_phenotypes:
  - preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: clinicaltrials:NCT04034550
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "COLEPT is a prospective interventional study that intends to better inform about leptospirosis, a neglected zoonotic infectious disease."
    explanation: Supports an active cohort-style clinical trial infrastructure for longitudinal human leptospirosis phenotyping.
epidemiology:
- name: Estimated annual global case burden
  description: Contemporary reviews estimate over one million infections globally each year.
  minimum_value: 1000000
  unit: cases_per_year
  evidence:
  - reference: DOI:10.3389/fmicb.2024.1403765
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leptospirosis, one of the most common global zoonotic infections, significantly impacts global human health, infecting more than a million people and causing approximately 60,000 deaths annually."
    explanation: Supports large annual global case burden.
- name: Estimated annual global mortality burden
  description: Annual global mortality is estimated at approximately sixty thousand deaths.
  minimum_value: 60000
  unit: deaths_per_year
  evidence:
  - reference: DOI:10.3389/fmicb.2024.1403765
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leptospirosis, one of the most common global zoonotic infections, significantly impacts global human health, infecting more than a million people and causing approximately 60,000 deaths annually."
    explanation: Supports substantial annual global mortality burden.
- name: Confirmed-case fatality in prospective febrile cohort
  description: In one prospective PCR-confirmed cohort, fatality was 2.7%.
  minimum_value: 2.7
  unit: percent
  evidence:
  - reference: DOI:10.1371/journal.pntd.0012449
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One confirmed case died resulting in a fatality of 2.7% (95% CI 0.5-13.8)."
    explanation: Provides cohort-level fatality estimate in confirmed acute cases.
- name: Leptospirosis among tropical infectious causes of acute kidney injury
  description: Leptospirosis is recognized among major tropical infectious causes of community-acquired acute kidney injury.
  evidence:
  - reference: PMID:28088326
    reference_title: "Acute kidney injury due to tropical infectious diseases and animal venoms: a tale of 2 continents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This article reviews the epidemiology, clinical picture, prevention, risk factors, and pathophysiology of acute kidney injury associated with tropical diseases (malaria, dengue, leptospirosis, scrub typhus, and yellow fever)"
    explanation: Supports placement of leptospirosis in the major tropical infection-AKI disease group.
- name: Reported mortality in ECLS-treated severe leptospirosis cases
  description: In published ECLS-treated severe cases, reported overall mortality was 16% (selected critical-care population).
  minimum_value: 16
  unit: percent
  evidence:
  - reference: DOI:10.3138/jammi-2023-0033
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Literature review identified 25 articles containing 43 reported cases of patients treated with ECLS for severe leptospirosis. Patients were mostly young and male. Overall mortality was 16%."
    explanation: Supports a quantified mortality estimate for the severe ECLS-treated subgroup.
differential_diagnoses:
- name: Acute bacterial sepsis
  description: Sepsis is a life-threatening cause of acute undifferentiated fever that overlaps clinically with severe leptospirosis.
  distinguishing_features:
  - Rapid progression with early organ dysfunction markers (e.g., altered consciousness, bleeding, oliguria, and abnormal breathing) signals high short-term mortality risk in AUF presentations.
  - Requires urgent broad diagnostic and treatment pathways while leptospirosis-specific testing is pending.
  disease_term:
    preferred_term: acute bacterial sepsis
    term:
      id: MONDO:0005229
      label: bacterial infectious disease with sepsis
  evidence:
  - reference: PMID:36130240
    reference_title: "Clinical features and risk factors for death in acute undifferentiated fever: A prospective observational study in rural community hospitals in six states of India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BACKGROUND: Acute undifferentiated fever (AUF) ranges from self-limiting illness to life-threatening infections, such as sepsis, malaria, dengue, leptospirosis and rickettsioses. Similar clinical presentation challenges the clinical management."
    explanation: Supports sepsis as a core disease-level differential in AUF settings where leptospirosis is considered.
  - reference: PMID:36130240
    reference_title: "Clinical features and risk factors for death in acute undifferentiated fever: A prospective observational study in rural community hospitals in six states of India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bleeding, cerebral dysfunction, respiratory failure and oliguria at admission, suggestive of severe organ failure secondary to systemic infection, were predictors of death."
    explanation: Supports severe systemic infection features that complicate distinction from severe leptospirosis at presentation.
- name: Rickettsioses
  description: Rickettsial infections are recognized causes of AUF that may be clinically indistinguishable from leptospirosis at initial presentation.
  distinguishing_features:
  - Shared AUF syndromic presentation commonly necessitates broad tropical fever testing rather than syndrome-based exclusion.
  disease_term:
    preferred_term: rickettsioses
    term:
      id: MONDO:0006956
      label: Rickettsiosis
  evidence:
  - reference: PMID:36130240
    reference_title: "Clinical features and risk factors for death in acute undifferentiated fever: A prospective observational study in rural community hospitals in six states of India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BACKGROUND: Acute undifferentiated fever (AUF) ranges from self-limiting illness to life-threatening infections, such as sepsis, malaria, dengue, leptospirosis and rickettsioses. Similar clinical presentation challenges the clinical management."
    explanation: Supports rickettsioses as a specific differential diagnosis within AUF cohorts that include leptospirosis.
- name: Dengue fever
  description: Dengue can closely overlap with leptospirosis in acute undifferentiated fever presentations and regional travel contexts.
  distinguishing_features:
  - In returning-traveler settings, dengue is especially common after Southeast Asia travel.
  - Overlap with leptospirosis in AUF requires context-aware testing rather than symptom-only separation.
  disease_term:
    preferred_term: dengue fever
    term:
      id: MONDO:0005502
      label: dengue disease
  evidence:
  - reference: PMID:36130240
    reference_title: "Clinical features and risk factors for death in acute undifferentiated fever: A prospective observational study in rural community hospitals in six states of India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BACKGROUND: Acute undifferentiated fever (AUF) ranges from self-limiting illness to life-threatening infections, such as sepsis, malaria, dengue, leptospirosis and rickettsioses. Similar clinical presentation challenges the clinical management."
    explanation: Supports dengue as a key overlapping febrile differential in settings where leptospirosis is evaluated.
  - reference: PMID:35469592
    reference_title: "Fever in the Returning Traveler."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among persons returning from travel to Southeast Asia, dengue fever is the most common infectious disease, affecting 50-160 per 1000 travelers."
    explanation: Supports dengue as a practical travel-related competing diagnosis in febrile syndromes overlapping leptospirosis.
- name: Plasmodium falciparum malaria
  description: Falciparum malaria is a high-priority differential in febrile illness and may overlap clinically with leptospirosis.
  distinguishing_features:
  - In returning travelers, falciparum malaria is a leading cause of fever after sub-Saharan Africa travel.
  - Early malaria-focused testing is critical in AUF because bedside clinical overlap with leptospirosis is substantial.
  disease_term:
    preferred_term: Plasmodium falciparum malaria
    term:
      id: MONDO:0005920
      label: Plasmodium falciparum malaria
  evidence:
  - reference: PMID:36130240
    reference_title: "Clinical features and risk factors for death in acute undifferentiated fever: A prospective observational study in rural community hospitals in six states of India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BACKGROUND: Acute undifferentiated fever (AUF) ranges from self-limiting illness to life-threatening infections, such as sepsis, malaria, dengue, leptospirosis and rickettsioses. Similar clinical presentation challenges the clinical management."
    explanation: Supports malaria as a core acute febrile differential alongside leptospirosis.
  - reference: PMID:35469592
    reference_title: "Fever in the Returning Traveler."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among travelers returning from sub-Saharan Africa, Plasmodium falciparum malaria is the most common cause of fever on presentation to centers for infectious diseases and tropical medicine, affecting approximately 50 per 1000 travelers."
    explanation: Supports falciparum malaria as a high-priority differential in travel-associated febrile presentations.
datasets:
- accession: geo:GSE72946
  title: Cathelicidin insufficiency in patients with fatal leptospirosis
  description: >-
    Human whole-blood transcriptome microarray dataset in acute leptospirosis,
    designed to identify molecular signatures associated with case fatality.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 33
  conditions:
  - acute leptospirosis
  - convalescent leptospirosis
  - healthy volunteers
  publication: PMID:27812211
  evidence:
  - reference: GEO:GSE72946
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole blood transcriptional profiling of Brazilian patients with acute leptospirosis to identify mechanisms associated with case fatality"
    explanation: Supports use of this human dataset for severity-linked host-response analyses.
- accession: geo:GSE86630
  title: Antibody profile in patients with mild and severe leptospirosis
  description: >-
    Human antibody-profiling dataset comparing mild and severe leptospirosis to
    define outcome-associated humoral immune signatures and candidate vaccine or
    diagnostic targets.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: PROTEOMICS
  conditions:
  - mild leptospirosis
  - severe leptospirosis
  evidence:
  - reference: GEO:GSE86630
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the antibodyrepertoire varies in patients with different clinical outcomes"
    explanation: Supports this dataset as a human severity-stratified immunoprofiling resource relevant to clinical heterogeneity.
- accession: geo:GSE53818
  title: A Model System for Studying the Transcriptomic and Physiological Changes Associated with Mammalian Host-Adaptation by Leptospira interrogans Serovar Copenhageni
  description: >-
    RNA-seq dataset comparing L. interrogans in host-adapted rat DMC conditions
    versus in vitro culture to identify mammalian host-adaptation programs.
  organism:
    preferred_term: Leptospira interrogans
    term:
      id: NCBITaxon:173
      label: Leptospira interrogans
  data_type: BULK_RNA_SEQ
  sample_count: 6
  conditions:
  - in vivo host-adapted DMC (rat peritoneal cavity)
  - in vitro cultured leptospires
  publication: PMID:24626166
  evidence:
  - reference: GEO:GSE53818
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "To obtain a more faithful representation of how leptospires respond to host-derived signals, we used RNA-Seq to compare the transcriptome of L. interrogans cultivated within dialysis membrane chambers (DMCs) implanted into the peritoneal cavities of rats with that of organisms grown in vitro."
    explanation: Supports this dataset as a key resource for host-adaptation pathophysiology.
- accession: geo:GSE105104
  title: MicroRNA profiles of murine macrophages infected with different strains of Leptospira spp
  description: >-
    Murine macrophage microRNA profiling dataset contrasting infection by virulent,
    attenuated, and saprophytic Leptospira strains.
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: MICROARRAY
  sample_count: 12
  conditions:
  - non-infected control macrophages
  - virulent-strain infection
  - attenuated-strain infection
  - saprophytic-strain infection
  publication: PMID:30129936
  evidence:
  - reference: GEO:GSE105104
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we suggest that post-transcriptional regulation, mediated by miRNAs, may play a role in host response to infection in leptospirosis in a species and virulence-specific manner."
    explanation: Supports this dataset for host-cell regulatory response mechanisms.
notes: >-
  Initial curation synthesized from AI-assisted deep research and
  reference-cache-grounded evidence, with emphasis on mechanistic granularity
  and clinically actionable diagnosis/treatment pathways.
review_notes: Updated with 2026 mechanistic evidence adding VM protein-driven epithelial junction disruption, cGAS-STING-dependent type I interferon host defense, and VE-cadherin endothelial injury as upstream vascular-pathology steps.