Dengue

Infectious Disease MONDO:0005502 Pathograph 12 Show in embeddings browser Arbovirus Infection Neglected tropical disease

Dengue is a mosquito-borne viral disease caused by dengue virus and transmitted by Aedes mosquitoes, with severe cases characterized by plasma leakage and shock.

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Discussions and Knowledge Gaps

1
Do the complement, macrophage and immune-checkpoint transcriptional signatures reported in pediatric dengue PBMCs correspond to actual changes in complement pathway activity, macrophage activation state, and lymphocyte effector function - and do any of them cause, rather than merely accompany, severe dengue?
KNOWLEDGE GAP OPEN gap_dengue_pbmc_transcriptomic_signatures_functional_validation
Attached to
pathophysiology#Complement Cascade Dysregulation pathophysiology#Macrophage-Mediated Innate Immune Activation pathophysiology#Immune Checkpoint-Mediated T Cell Exhaustion in Secondary Dengue
All three nodes rest on a single bulk PBMC RNA-seq study of nine children (n = 3 primary, n = 3 secondary, n = 3 healthy controls), with no serotyping and no functional assay. The authors twice flag the limits of what the data can establish: they state that "activation" denotes the direction of differential gene expression rather than biochemical complement activity, and the abstract calls the signatures preliminary and in need of systematic functional validation. Bulk PBMC expression also confounds cell-composition shifts with per-cell state changes, so an apparent macrophage-activation signature may partly reflect monocyte frequency. The ModifierEnum values on these nodes should therefore be read as transcript-level, and no causal edge to disease severity is asserted from them. Two further limits are specific to the primary-versus-secondary contrast, which is the comparison the secondary-infection arms of these nodes rest on. First, none of the complement-pathway genes reached significance in that contrast after multiple-testing correction, so the reported "transition from activation to regulation" is a nominal trend. Second, the paper's Results and Discussion sections disagree on the direction of LAG3, TIGIT and CD96 in secondary dengue. Both are recorded in the `notes` of the affected nodes; resolving either needs an independent cohort rather than reanalysis of these nine samples.
Proposed experiments
Functional complement readout paired with the transcriptional signature
prospective clinical cohort with paired transcriptomic and functional complement assays Relation: this experiment is of type this experiment type This experiment is of type prospective clinical cohort with paired transcriptomic and functional complement assays.
exp_dengue_complement_functional_readout
In a larger, serotyped pediatric dengue cohort spanning non-severe and severe disease, pair PBMC transcriptomics with plasma complement activation-product measurement (C3a, C5a, sC5b-9, Bb) and functional pathway assays, sampled longitudinally across the febrile, critical and convalescent phases. This tests whether the transcriptional "activation to regulation" shift tracks measured complement turnover.
Decision criterion
Concordance between the direction of complement transcript change and measured plasma activation products, and association of the activation products with plasma leakage severity.
Would support
pathophysiology#Complement Cascade Dysregulation
Would refute
pathophysiology#Complement Cascade Dysregulation
Supporting outcome
  • Measured complement activation products track the transcriptional signature and scale with plasma leakage, converting this node from a transcript-level observation into a measured mechanism and grounding its edge to plasma leakage.
Refuting outcome
  • Complement activation products are unchanged or discordant with the transcript direction, indicating the signature is a bystander readout and that the modifier on this node should not be read as pathway activity.
Single-cell and functional test of the checkpoint-exhaustion signature
single-cell multi-omic profiling with ex vivo functional lymphocyte assays Relation: this experiment is of type this experiment type This experiment is of type single-cell multi-omic profiling with ex vivo functional lymphocyte assays.
exp_dengue_checkpoint_exhaustion_functional_assay
Apply single-cell RNA-seq with surface-protein profiling to separate cell-composition shifts from per-cell state changes, and test exhaustion functionally in NK, MAIT and T cells from primary versus secondary pediatric dengue - antigen-stimulated cytokine production, proliferation and cytotoxicity, with and without PD-1/LAG3/TIGIT blockade ex vivo.
Decision criterion
Reduced effector function in checkpoint-high lymphocytes from secondary dengue, partially restored by checkpoint blockade ex vivo.
Would support
pathophysiology#Immune Checkpoint-Mediated T Cell Exhaustion in Secondary Dengue
Would refute
pathophysiology#Immune Checkpoint-Mediated T Cell Exhaustion in Secondary Dengue
Supporting outcome
  • Checkpoint-high NK/MAIT/T cells show measurably impaired effector function that is partially reversible, establishing exhaustion rather than transcript upregulation alone.
Refuting outcome
  • Effector function is preserved despite checkpoint upregulation, indicating transient activation-associated checkpoint expression rather than exhaustion, and requiring this node to be reframed.
Antibody-dependent enhancement (ADE) is the canonical driver of secondary-dengue severity and is covered in this entry's deep-research artifacts, but is not yet modelled as a pathophysiology node. An ADE node would be the natural upstream anchor for these three secondary-infection nodes; that is a separate curation increment.
Show evidence (1 reference)
PMID:42603814 SUPPORT Human clinical
"While our initial findings provide early insights into the transcriptional patterns potentially associated with disease outcomes, the dysregulated transcriptomic signatures reported here are preliminary requiring systemic functional validation to determine their biologic role in the..."
The authors' own statement that the signatures underlying these three nodes are preliminary and require functional validation.
⚙

Pathophysiology

12
Antibody-Dependent Enhancement in Secondary Heterotypic Infection
Secondary infection with a heterotypic dengue virus serotype can enhance disease severity through antibody-dependent enhancement, in which non-neutralizing antibodies from the primary infection promote increased viral uptake and immune dysregulation.
Downstream
Plasma Leakage ADE-driven immune activation and cytokine dysregulation contribute to the vascular permeability underlying severe-dengue plasma leakage.
Show evidence (2 references)
PMID:34171205 SUPPORT Other
"the severity of the disease is enhanced via heterotypic infection by various serotypes as well as antibody-dependent enhancement (ADE)"
Review states heterotypic serotype infection and ADE enhance dengue disease severity.
PMID:32265181 SUPPORT Other
"antibody-dependent enhancement, cytokine dysregulation and variation of lipid profiles are correlated with DHF occurrence"
Review correlates antibody-dependent enhancement with DHF occurrence.
Natural Killer Cell-Mediated Antibody-Dependent Cellular Cytotoxicity
IgG antibodies (particularly IgG1) bound to dengue-infected cells engage Fcγ receptor IIIa (CD16a) on natural killer cells, triggering release of cytolytic molecules. This results in killing of DENV-infected cells, a protective effector function correlating with lower viremia in secondary infections.
natural killer cell CL:0000623 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves natural killer cell (CL:0000623). CL:0000623 is a cell type from the Cell Ontology.
antibody-dependent cellular cytotoxicity GO:0001788 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves antibody-dependent cellular cytotoxicity (GO:0001788). GO:0001788 is a biological process from the Gene Ontology. natural killer cell mediated cytotoxicity GO:0042267 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves natural killer cell mediated cytotoxicity (GO:0042267). GO:0042267 is a biological process from the Gene Ontology.
Show evidence (3 references)
PMID:42773233 SUPPORT REVIEW SYNTHESIS In vitro / ex vivo
"ADCC, where IgG antibodies bind viral antigens on DENV-infected cells and trigger killing of infected cells by natural killer cells through engagement of FcγRIIIa (CD16a)"
Grounds the effector cell and the FcγRIIIa/CD16a receptor this node names; the review's synthesis of experimental work it did not perform.
PMID:42773233 SUPPORT REVIEW SYNTHESIS Human clinical
"This prospective study reported that high levels of preexisting anti-DENV IgG1 were associated with ADCC, which correlated with lower plasma viraemia during secondary DENV infections"
Prospective cohort in which ADCC activity correlates with reduced viraemia; the quote reports an association and does not itself identify the effector cell.
PMID:42773233 SUPPORT REVIEW SYNTHESIS In vitro / ex vivo
"direct evidence for ADCC in dengue comes primarily from in vitro experimental studies and an early paediatric study conducted in Thailand"
Records the evidence base behind this node, bounding how far the human cohort association can be read as a mechanism in patients.
Monocyte-Dependent Antibody-Dependent Cellular Phagocytosis
Antibodies opsonize dengue virions and infected cells, promoting their uptake and clearance by Fc receptor-expressing monocytes and macrophages. ADCP targets both structural (prM, E) and non-structural (NS1) proteins. Phagocytic uptake did not result in accumulation of DENV genomic material within monocytes, suggesting it does not drive productive infection within phagocytes.
monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology. macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
Fc-gamma receptor signaling pathway involved in phagocytosis GO:0038096 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Fc-gamma receptor signaling pathway involved in phagocytosis (GO:0038096). GO:0038096 is a biological process from the Gene Ontology.
Show evidence (4 references)
PMID:42773233 SUPPORT REVIEW SYNTHESIS In vitro / ex vivo
"ADCP involves the opsonisation of virions or infected cells with antibodies, usually IgG, leading to their uptake and clearance by Fcγ receptor-expressing phagocytes such as monocytes. Studies have reported that antibodies that promote ADCP can target both structural and non-structural proteins of DENV."
Review's synthesis of cell-culture work describing the phagocytic effector route and the breadth of antigens that engage it.
PMID:42773233 SUPPORT REVIEW SYNTHESIS In vitro / ex vivo
"Monoclonal antibodies targeting prM and envelope epitopes promoted ADCP of DENV-infected cells by peripheral blood mononuclear cells"
Grounds the structural-protein half of this node's antigen claim (prM and E).
PMID:42773233 SUPPORT REVIEW SYNTHESIS In vitro / ex vivo
"Using recombinant monoclonal IgG and IgA antibodies against NS1, the authors demonstrated that these antibodies can mediate ADCP through engagement of FcγRI (CD64) and FcαRI (CD89)"
Grounds the non-structural (NS1) half of the antigen claim, and names the Fc receptors through which phagocytosis proceeds.
+ 1 more reference
Complement-Mediated Antibody-Dependent Virolysis
Antibodies bound to dengue virions activate the classical complement cascade via C1q recruitment, depositing complement components on virions and infected cells. This leads to lysis of both free virions and infected cells. ADCD correlates with asymptomatic dengue outcomes.
complement activation, classical pathway GO:0006958 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves complement activation, classical pathway (GO:0006958). GO:0006958 is a biological process from the Gene Ontology. complement-dependent cytotoxicity GO:0097278 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves complement-dependent cytotoxicity (GO:0097278). GO:0097278 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:42773233 SUPPORT REVIEW SYNTHESIS Human clinical
"higher ADCD activities against virions and infected cells were observed in children with inapparent infection compared with symptomatic infection, suggesting a protective role in the ADCD pathway"
Clinical observation showing complement-dependent functions correlate with asymptomatic outcomes.
PMID:42773233 SUPPORT REVIEW SYNTHESIS In vitro / ex vivo
"deposition of complement components (C1q) on virions or infected cells, leading to virolysis or complement-mediated lysis of infected cells"
Grounds the C1q deposition and lysis steps this node describes; the source stops here and does not describe a membrane attack complex in dengue.
IgA-Mediated Neutralization and Blockade of Antibody-Dependent Enhancement
Dengue-specific IgA antibodies provide protection through direct neutralization and blockade of IgG-mediated antibody-dependent enhancement. The absence of enhanced inflammation is reported for human macrophage cultures exposed to IgA-DENV complexes, and does not extend to IgA responses generally: anti-NS1 IgA raised by prior Zika infection is associated with increased risk of severe DENV-2 disease through neutrophil Fc-alpha receptor engagement.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
immunoglobulin mediated immune response GO:0016064 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves immunoglobulin mediated immune response (GO:0016064). GO:0016064 is a biological process from the Gene Ontology.
Show evidence (3 references)
PMID:42773233 SUPPORT REVIEW SYNTHESIS In vitro / ex vivo
"DENV-specific IgA can display neutralising function and block IgG-mediated ADE"
Review's synthesis of cell-culture work establishing the two protective IgA functions this node asserts.
PMID:42773233 SUPPORT REVIEW SYNTHESIS In vitro / ex vivo
"In human macrophage cultures, IgA-DENV complexes did not induce ADE or enhance inflammation, which otherwise may predispose to severe dengue"
The system in which the absence of enhancement was shown, which is why this node's description names the culture rather than IgA responses in general.
PMID:42773233 REFUTE REVIEW SYNTHESIS Human clinical
"It was demonstrated that IgA antibodies, specifically anti-NS1 IgA induced after primary Zika virus infection, are associated with increased risk of severe DENV-2 infection"
The same review documents a pathogenic IgA route, so it contradicts any general reading of this node as IgA being uniformly protective; it bounds the claim rather than removing it.
NS1-Induced Endothelial Glycocalyx Degradation
Secreted dengue NS1 acts directly on vascular endothelium: it induces sialidase and heparanase expression and activates cathepsin L, which together strip sialic acid and shed heparan sulfate proteoglycans from the endothelial glycocalyx layer. Loss of that layer is an endothelial cell-intrinsic route to hyperpermeability, separate from the antibody- and cytokine-mediated arm above.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
Downstream
Plasma Leakage Stripping the endothelial glycocalyx removes a principal regulator of endothelial barrier function, and the resulting hyperpermeability is the cell-intrinsic mechanism of plasma leakage.
Show evidence (2 references)
PMID:27416066 SUPPORT In vitro / ex vivo
"Here, we demonstrate that DENV NS1 disrupts the EGL on human pulmonary microvascular endothelial cells, inducing degradation of sialic acid and shedding of heparan sulfate proteoglycans."
Demonstrates the glycocalyx degradation this node asserts, on human endothelial cells.
PMID:27416066 SUPPORT In vitro / ex vivo
"This effect is mediated by NS1-induced expression of sialidases and heparanase, respectively."
Identifies the sialidase and heparanase route named in this node's description.
Plasma Leakage
Increased vascular permeability allows plasma to escape the intravascular compartment into the pleural and peritoneal spaces, with hemoconcentration. This is the pathophysiological hallmark that separates dengue hemorrhagic fever from uncomplicated dengue fever.
Downstream
Hypovolemic Shock When leakage is severe enough, the loss of circulating volume produces hypovolemic shock. Splitting this from the leakage node matters therapeutically: fluid resuscitation acts on the volume loss, not on the permeability that caused it.
Show evidence (1 reference)
PMID:32265181 SUPPORT Other
"Plasma leakages is the main pathophysiological hallmark that distinguishes DHF from DF."
Identifies plasma leakage as the defining mechanism of the severe form.
Hypovolemic Shock
Loss of intravascular volume to the extravascular space produces circulatory failure. This is the node fluid resuscitation acts on, and the mechanism behind the dengue shock syndrome presentation.
Downstream
Dengue Shock Syndrome Hypovolemic shock arising from dengue plasma leakage is the clinical presentation named dengue shock syndrome.
Show evidence (1 reference)
PMID:16135832 SUPPORT Human clinical
"Dengue shock syndrome is characterized by severe vascular leakage and disordered hemostasis and progresses to death in 1 to 5 percent of cases."
Characterizes the shock state and its mortality.
Platelet Activation and Accelerated Platelet Clearance
Circulating platelets carry DENV genome and become activated, acquiring surface complement C3 and IgG and being phagocytosed by monocytes. Platelet counts fall around day 4 of fever and recover from day 6 to day 10, tracking the activation markers.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
Downstream
Thrombocytopenia Activated platelets are cleared faster than they are replaced, which is what the falling platelet count measures.
Hemorrhagic Manifestations Platelet depletion contributes to the bleeding tendency, alongside the disordered hemostasis reported in severe dengue. The intermediates are not resolved here, so the link is not typed as direct.
Show evidence (1 reference)
PMID:28139770 SUPPORT Human clinical
"we described a direct correlation between activation and depletion of platelets in patients"
Establishes the activation-to-depletion relationship in dengue patients.
Complement Cascade Dysregulation
Transcriptional signature of complement dysregulation in pediatric dengue: classical and lectin pathway components are upregulated during primary infection with concurrent downregulation of several complement regulators (FDR-significant). The primary-versus-secondary comparison shows a nominal trend toward the reciprocal pattern (C1QA/C1QC/C2/C4b down, CFI/C4BP/MBL2/CFP up), which the authors interpret as a transition from activation to regulation in secondary infection, though this comparison did not reach FDR significance.
complement activation GO:0006956 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased complement activation (GO:0006956). GO:0006956 is a biological process from the Gene Ontology.
Downstream
Plasma Leakage Excessive or unbalanced complement activation is proposed to increase vascular permeability and drive the plasma leakage that defines severe dengue. The intermediates linking complement activation products to endothelial barrier failure are not established in this cohort.
Show evidence (2 references)
PMID:42603814 SUPPORT Human clinical
"Multiple classical and lectin pathway genes were upregulated in the primary dengue cohort, including MBL2, C1QA, C1QB, C1QC, C2, and C9 (Fig. 3). In contrast, several complement regulatory factors were downregulated in the primary dengue cohort, including CD93, properdin (CFP), CR1, SERPING,..."
PBMC transcriptomics from a WHO-classified pediatric dengue cohort shows coordinated upregulation of classical and lectin pathway transcripts with downregulation of regulator transcripts in primary infection.
PMID:42603814 SUPPORT Human clinical
"Further analysis of the primary vs secondary dengue cohort data revealed a widespread downregulation of C1QA, C1QC, C2, and C4b accompanied by upregulation of CFI, C4BP, MBL2, and CFP, which suggests a transition from activation to regulation"
PARTIAL rather than SUPPORT - the authors explicitly note that this primary-versus-secondary comparison is based on nominal expression trends rather than FDR-significant differential expression, as none of the complement genes met the FDR < 0.05 threshold in the direct comparison.
Macrophage-Mediated Innate Immune Activation
Transcriptional signature of macrophage activation in both primary and secondary pediatric dengue, marked by elevated expression of macrophage-associated markers (ITGB2, SPP1, KLF6) and tissue-remodelling genes, with concurrent downregulation of the pro-inflammatory mediators S100A8 and BATF that the authors read as feedback restraint.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
macrophage activation GO:0042116 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased macrophage activation (GO:0042116). GO:0042116 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:42603814 SUPPORT Human clinical
"The upregulation of macrophage-associated markers (ITGb2, SPP1, and KLF6) across both primary as well as secondary dengue affirms robust macrophage activation and tissue remodelling. The downregulation of S100A8 and BATF appears to represent feedback restrain exaggerated inflammation."
PBMC transcriptomics from a pediatric dengue cohort shows coordinated upregulation of macrophage-associated transcripts alongside downregulation of two pro-inflammatory mediators.
Immune Checkpoint-Mediated T Cell Exhaustion in Secondary Dengue
Transcriptional signature of immune-checkpoint upregulation (PDCD1/PD-1, LAG3, TIGIT, CD96, VSIG4) in pediatric dengue, markedly higher in secondary than in primary infection, which the authors interpret as immune exhaustion of NK, MAIT and T cells restricting antiviral effector function.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology. natural killer cell CL:0000623 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves natural killer cell (CL:0000623). CL:0000623 is a cell type from the Cell Ontology. mucosal-associated invariant T (MAIT) cell CL:0000940 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mucosal-associated invariant T (MAIT) cell, annotated with mucosal-associated invariant T cell (CL:0000940). CL:0000940 is a cell type from the Cell Ontology.
checkpoint-mediated restraint of T cell activation GO:0050868 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased checkpoint-mediated restraint of T cell activation, annotated with negative regulation of T cell activation (GO:0050868). GO:0050868 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:42603814 SUPPORT Human clinical
"Immune checkpoint, including PDCD1, LAG3, TIGIT, CD96, and VSIG4, were upregulated in both primary and secondary pediatric dengue, with markedly higher expressions in the secondary cohort. This enhanced checkpoint activity aligns with the immune exhaustion observed in NK cells, MAIT cells, and T..."
PBMC transcriptomics shows checkpoint-molecule transcripts upregulated in both cohorts and markedly higher in secondary infection, the study's most consistent primary-versus-secondary difference.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Dengue Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

5
Blood 2
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34171205 SUPPORT Other
"Clinical symptoms of dengue range from mild fever to severe dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), with thrombocytopenia, leucopenia, and increased vascular permeability."
The review lists thrombocytopenia as part of the clinical symptom spectrum of dengue, including severe forms (DHF/DSS).
Hemorrhagic Manifestations Abnormal bleeding HP:0001892 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemorrhagic manifestations, annotated with Abnormal bleeding (HP:0001892). HP:0001892 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39773842 SUPPORT Other
"In Dengue, distinctive rashes like the 'islands of white in a sea of red' and hemorrhagic skin manifestations have been key diagnostic features."
Names hemorrhagic skin manifestations as a diagnostic feature of dengue.
PMID:16135832 SUPPORT Human clinical
"Dengue shock syndrome is characterized by severe vascular leakage and disordered hemostasis and progresses to death in 1 to 5 percent of cases."
Documents disordered hemostasis as a defining feature of the severe form.
Cardiovascular 1
Dengue Shock Syndrome Hypovolemic shock HP:0031274 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dengue shock syndrome, annotated with Hypovolemic shock (HP:0031274). HP:0031274 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16135832 SUPPORT Human clinical
"Dengue shock syndrome is characterized by severe vascular leakage and disordered hemostasis and progresses to death in 1 to 5 percent of cases."
Randomized-trial report characterizing dengue shock syndrome as severe vascular leakage with substantial mortality.
Immune 1
Skin rash FREQUENT HP:0000988 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin rash (HP:0000988). HP:0000988 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39773842 SUPPORT Other
"In Dengue, distinctive rashes like the 'islands of white in a sea of red' and hemorrhagic skin manifestations have been key diagnostic features."
The dermatology review identifies the characteristic dengue rash ("islands of white in a sea of red") as a key diagnostic feature.
Metabolism 1
Fever VERY_FREQUENT HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34171205 SUPPORT Other
"Clinical symptoms of dengue range from mild fever to severe dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), with thrombocytopenia, leucopenia, and increased vascular permeability."
The review lists fever as the defining clinical symptom across the dengue disease spectrum.
💊

Medical Actions

2
Intravenous Fluid Resuscitation
Action: fluid therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is fluid therapy (NCIT:C116537). NCIT:C116537 is a clinical intervention from the NCI Thesaurus. Ontology label: Fluid Therapy NCIT:C116537
Platform: Other
Timely intravenous fluid resuscitation is the critical supportive intervention for dengue shock syndrome; WHO management guidelines for fluid choice remain largely empirical.
Mechanism Target:
RESTORES Hypovolemic Shock — Fluid resuscitation restores the intravascular volume lost to vascular leakage. It acts on the shock consequence, not on the permeability that produced it, which is why it targets this node rather than Plasma Leakage.
Show evidence (1 reference)
PMID:16135832 SUPPORT Human clinical
"Although volume replacement is recognized as the critical therapeutic intervention, World Health Organization management guidelines remain empirical rather than evidence-based."
Randomized trial identifies volume replacement as the critical intervention for dengue shock syndrome.
Show evidence (1 reference)
PMID:16135832 SUPPORT Human clinical
"Although volume replacement is recognized as the critical therapeutic intervention, World Health Organization management guidelines remain empirical rather than evidence-based."
Randomized trial identifies volume replacement as the critical intervention for dengue shock syndrome.
Tetravalent Live-Attenuated Dengue Vaccination (TAK-003 / CYD-TDV)
Action: VaccinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Vaccination (NCIT:C15346). NCIT:C15346 is a clinical intervention from the NCI Thesaurus. NCIT:C15346
Platform: Vaccine
Active immunization with tetravalent live-attenuated dengue vaccines — the DENV-2-backboned TAK-003 (Qdenga) or the yellow fever 17D-backboned chimeric CYD-TDV (Dengvaxia) — elicits neutralizing antibodies against all four DENV serotypes and, for TAK-003, non-structural protein (NS1) humoral and cellular immunity that limits viremia and prevents severe endothelial glycocalyx disruption. Clinical deployment is critically modified by baseline dengue serostatus: CYD-TDV lacks DENV NS1 antigens and sensitized baseline-seronegative vaccinees to antibody-dependent enhancement and increased hospitalization risk upon primary wild-type infection, restricting its indication to laboratory-confirmed seropositive individuals, whereas TAK-003 demonstrated 4.5-year efficacy and safety against all four serotypes in baseline-seropositive individuals and against DENV-1 and DENV-2 in baseline-seronegative individuals.
Mechanism Target:
ACTIVATES IgA-Mediated Neutralization and Blockade of Antibody-Dependent Enhancement — Tetravalent vaccination aims to induce balanced neutralizing antibodies across all four dengue serotypes so that virions are neutralized before subneutralizing IgG complexes can engage Fc-gamma receptors to drive antibody-dependent enhancement.
Show evidence (1 reference)
PMID:29482433 SUPPORT INDIRECT Human clinical
"There is general agreement that DENV vaccines should ideally induce protective neutralizing antibodies to each of the four serotypes simultaneously."
Establishes the mechanistic rationale that balanced tetravalent neutralizing immunity is required to prevent antibody-dependent enhancement across the four DENV serotypes.
INHIBITS NS1-Induced Endothelial Glycocalyx Degradation — By suppressing dengue viral replication and, in DENV-backboned vaccines such as TAK-003, priming anti-NS1 immunity, vaccination reduces circulating DENV NS1 antigen levels and downstream endothelial glycocalyx degradation and hospitalized plasma-leakage disease.
Show evidence (1 reference)
PMID:38245116 SUPPORT INDIRECT Human clinical
"Cumulative vaccine efficacy was 61·2% (95% CI 56·0-65·8) against virologically confirmed dengue and 84·1% (77·8-88·6) against hospitalised virologically confirmed dengue; corresponding efficacies were 53·5% (41·6-62·9) and 79·3% (63·5-88·2) in baseline seronegative participants (safety set)."
Phase 3 4.5-year trial data showing 84.1% efficacy against hospitalized virologically confirmed dengue.
Effect differs by subgroup:
biomarker Baseline dengue-seronegative individuals (no prior DENV infection) vs Baseline dengue-seropositive individuals (prior DENV infection) — opposite effect on Risk of hospitalized virologically confirmed dengue and serotype breadth of vaccine efficacy
In baseline-seronegative children, the chimeric YF-17D/DENV vaccine CYD-TDV acted as a silent primary sensitization that predisposed recipients to vaccine-enhanced hospitalized dengue upon subsequent wild-type DENV infection, restricting CYD-TDV to individuals with prior dengue infection. In contrast, TAK-003 (built on an attenuated DENV-2 backbone retaining DENV NS1) showed no increased hospitalization risk in seronegative recipients over 4.5 years and protected baseline-seropositive individuals against all four serotypes and baseline-seronegative individuals against DENV-1 and DENV-2, but did not show efficacy against DENV-3 in baseline-seronegative individuals.
Show evidence (2 references)
PMID:29482433 SUPPORT Human clinical
"This surmise was validated recently when the manufacturer reported that dengue NS1 IgG antibodies were absent in sera from hospitalized vaccinated children, an observation consistent with their having received Dengvaxia when seronegative."
Demonstrates that breakthrough dengue hospitalizations after CYD-TDV occurred in individuals who were dengue-seronegative (lacking anti-NS1 IgG) at vaccination.
PMID:38245116 SUPPORT Human clinical
"In an exploratory analysis, vaccine efficacy was shown against all four serotypes in baseline seropositive participants. In baseline seronegative participants, vaccine efficacy was shown against DENV-1 and DENV-2 but was not observed against DENV-3 and low incidence precluded evaluation against DENV-4."
Establishes serotype- and serostatus-dependent efficacy of TAK-003 at 4.5 years in the phase 3 trial.
Show evidence (2 references)
PMID:38245116 SUPPORT Human clinical
"TAK-003 demonstrated long-term efficacy and safety against all four DENV serotypes in previously exposed individuals and against DENV-1 and DENV-2 in dengue-naive individuals."
Phase 3 randomized trial demonstrating 4.5-year efficacy and safety of tetravalent dengue vaccine TAK-003.
PMID:29482433 SUPPORT Human clinical
"In response to the recognized vulnerability of seronegatives, on 29 November 2017, Sanofi issued a press release stating that “For individuals who have not been previously infected by dengue virus, vaccination should not be recommended.”"
Documents the serostatus restriction of first-generation chimeric dengue vaccination (CYD-TDV) due to enhanced disease risk in baseline-seronegative recipients.
🔬

Diagnosis

2
Early virological diagnosis (NS1 antigen and dengue RNA)
In the first days of illness dengue is confirmed by detecting the virus itself: NS1 antigen by immunoassay or viral RNA by RT-PCR. Both are most sensitive in the viraemic phase (pooled estimates are for days 0-4 after symptom onset), when IgM is often not yet detectable; IgM serology takes over from day 5 of illness (see the serology row). The timing rule is the reason the tests are not interchangeable: a negative IgM in the first days does not exclude dengue.
dengue NS1 antigen LOINC:91064-6 Logical Observation Identifiers Names and Codes (LOINC) dengue virus RNA (RT-PCR) LOINC:7855-0 Logical Observation Identifiers Names and Codes (LOINC)
A Monarch KG search found no LOINC Part and no method-less code for dengue NS1 antigen or for dengue RNA. NS1 binds the serum-or-plasma presence code by immunoassay, the method every NS1 test uses (ELISA and rapid tests alike), rather than the rapid-immunoassay or quantitative variants (LOINC:75377-2 Dengue virus NS1 Ag [Presence] in Serum, Plasma or Blood by Rapid immunoassay; LOINC:101206-1 Dengue virus NS1 Ag [Units/volume] in Serum or Plasma by Immunoassay). RNA binds the pan-serotype serum presence code; every dengue RNA presence code in the KG names an amplification method, and the serotype-specific codes would make one test four. No reference_ranges: both results are qualitative and the cited sources state no diagnostic threshold.
Show evidence (3 references)
PMID:26118588 SUPPORT Human clinical
"RNA and NS1 were most valuable for early diagnosis of dengue, whereas IgM was best suited as a supplementary method for patients at day 5 or more after illness onset."
Diagnostic evaluation in 294 patients from the 2014 Guangzhou outbreak states the timing rule: RNA and NS1 early, IgM from day 5 of illness.
PMID:40209729 SUPPORT Human clinical
"Pooled sensitivities of RT-PCR (0-4 days after symptom onset), NS1 ELISA (0-4 days), and IgM ELISA (1-7 days) were 95% (95% credible interval 77-99), 90% (68-98), and 71% (57-84), respectively."
Meta-analysis of data from 161 articles gives the early-illness accuracy of RT-PCR and NS1 ELISA against the lower sensitivity of IgM ELISA in the first week.
PMID:40209729 SUPPORT Human clinical
"IgM ELISA shows poor diagnostic accuracy early in the symptom course. NS1 ELISA shows similar diagnostic accuracy to RT-PCR"
The meta-analysis' interpretation: NS1 antigen and RT-PCR are the comparable early tests, and IgM is poor early in illness.
Dengue IgM and IgG serology
Dengue-specific IgM antibody is the diagnostic test from day 5 of illness onward, when it performs better than in the first days. IgG antibody is read for the patient's immune status rather than to confirm the current episode: a positive IgG rapid test indicates a post-primary (secondary) infection, and a negative one on days 3-5 of fever indicates a primary one.
dengue IgM antibody LOINC:25338-5 Logical Observation Identifiers Names and Codes (LOINC) dengue IgG antibody LOINC:29676-4 Logical Observation Identifiers Names and Codes (LOINC)
Both measurements bind the method-less serum presence code rather than an immunoassay-, immunoblot- or rapid-test-specific sibling. No reference_ranges: IgM and IgG positivity cut-offs are set by each kit, and the cited sources define no disease-owned antibody threshold.
Show evidence (2 references)
PMID:26118588 SUPPORT Human clinical
"RNA had a better performance with 98.1% of sensitivity from day 1 to day 4 after illness onset. IgM performed better at day 5 or more with 74.0% of sensitivity."
Places IgM serology after the first four days of illness, when RNA detection is the more sensitive test.
PMID:35507552 SUPPORT Human clinical
"Overall, IgG RDT positive results were confirmatory of post-primary infections. In contrast, IgG RDT negative results were suggestive of both primary and post-primary infections on days 1-2 of fever, yet were confirmatory of primary infections on days 3-5 of fever."
Cross-sectional surveys of acute suspected dengue patients in Indonesia, Vietnam and the Philippines show what an IgG result says about primary versus post-primary infection by day of fever.
🦠

Infectious Agent

1
Dengue virus
Dengue virus comprises four antigenically distinct serotypes (DENV-1 through DENV-4); infection with one serotype confers lifelong homotypic immunity but only short-term cross-protection against the others.
Dengue virus NCBITaxon:12637 NCBI Taxonomy (NCBITaxon)
Show evidence (3 references)
PMID:34171205 SUPPORT
"Dengue is a vector-borne viral disease caused by the flavivirus dengue virus (DENV)."
The review identifies dengue virus as the causative flavivirus.
PMID:34171205 SUPPORT Other
"It has four antigenically distinct serotypes, DENV-1 to DENV-4, with different genotypes"
Establishes the four antigenically distinct DENV serotypes.
PMID:23817881 SUPPORT Other
"Infection with any one of the viruses is thought to provide lifetime immunity to future infections from the same virus but only short-term cross-immunity to the other types, leading to the possibility of secondary infections."
Documents lifelong homotypic immunity versus short-term heterotypic cross-immunity across the four serotypes.
↔️

Transmission

1
Aedes mosquito transmission
Aedes aegypti and Aedes albopictus transmit dengue virus to humans.
Show evidence (1 reference)
PMID:23817881 SUPPORT
"It is usually transmitted to humans through the bite of an infected Aedes aegypti or Aedes albopictus mosquito."
The abstract specifies Aedes aegypti and Aedes albopictus as vectors.
📊

Related Datasets

8
A population of CD4+CD8+ double-positive T cells associated with risk of plasma leakage in dengue viral infection geo:GSE178240
According to the WHO 2009 classification, dengue with warning signs (D+W) is at the risk of developing severe form of dengue disease. One of the most important warning signs is plasma leakage, which is a serious complication associated with higher morbidity and mortality. We report that the frequency of CD4+CD8+ double-positive (DP) T cells is significantly increased in patients at risk of developing plasma leakage. Transcriptomic analysis demonstrated that CD4+CD8+ DP cells were distinct from CD4+ Single Positive (SP) T cells, but co-clustered with CD8+ SP cells indicating a largely similar transcriptional profile.
human BULK RNA SEQ n=414
PMID:35062294
Identified by GEO DataSets index search for Dengue (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Vitamin D Enhances Antiviral Responses in Dengue Virus-Infected Macrophages by Modulating Early-Response Gene Expression geo:GSE297386
Dengue virus (DENV), the etiological agent of dengue fever, remains a global health concern, leading to severe illness and death in the absence of any definitive cure. Research has shown that vitamin D may reduce DENV replication in vitro and that dengue patients with low or deficient vitamin D levels are at higher risk of severe dengue. Studies indicate that viral replication is inhibited in human monocyte-derived macrophages (MDM) differentiated in the presence of vitamin D (D3MDM), suggesting that vitamin D may prevent DENV entry into host cells.
human BULK RNA SEQ n=24
PMID:40839599
Identified by GEO DataSets index search for Dengue (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Genome-wide gene expression analysis of human whole-blood samples in in response to dengue disease geo:GSE28405
We looked at the whole-blood transcriptional profiling on dengue patients sampled within 72h of fever presentation and compared the signatures with autologous samples drawn at defervescence and convalescence and to control patients with fever of other etiology. Our data show that the early response in patients mimics those previously only described in vitro and suggests that this innate immune responses may initiate the later adaptive immune responses.
human MICROARRAY n=119
PMID:21810247
Identified by GEO DataSets index search for Dengue (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
GWAS data (Illumina 2.5 M SNPs) in Cuban cohorts of dengue disease ega:EGAS00001002276
We will have 274 individuals typed for the Illumina Human Omni 2.5 chip. The individuals are from two locations in Cuba (Havana and Guantanamo) and from four phenotype classes (asymptomatic, control dengue fever and dengue hemorrhagic fever).
human
PMID:28241052
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Dengue"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
GWAS in a dengue Thai cohort ega:EGAS00001002756
Around 700,000 SNPs were genotyped in 290 controls, 252 dengue fever patients and 159 dengue shock syndrome patients from Thailand.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Dengue"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Establishment of germline-encoded antibodies during primary dengue infection ega:EGAS50000001944
This study supports the manuscript “Establishment of germline-encoded antibodies during primary dengue infection” and characterizes longitudinal B cell receptor repertoire dynamics during controlled primary DENV1 infection. Bulk BCR sequencing was performed on whole-blood total RNA from flavivirus-naïve participants in a DENV1 live-virus human challenge study. Samples were collected at days 0, 8, 10, 14, and 28 post-infection, corresponding to pre-infection, early viremic, peak viremic/acute, late viremic/critical-phase, and convalescent timepoints.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Dengue"); description-level mentions were not accepted. EGA study_type: Transcriptome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
TMEM41B and VMP1 modulate cellular lipid and energy metabolism for facilitating Dengue virus infection metabolomics_workbench:ST002164
Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Dengue"). Retrieved 2026-08-02.
mitochondrial and dengue virus_2023 massive:MSV000093299
Dengue virus non-structural protein 3 inhibits mitochondrial respiration by impairing complex I function
Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Dengue"). Retrieved 2026-08-02.
{ }

Source YAML

click to show 
name: Dengue
creation_date: '2025-12-04T16:57:31Z'
category: Infectious Disease
description: Dengue is a mosquito-borne viral disease caused by dengue virus and transmitted by Aedes mosquitoes, with severe cases characterized by plasma leakage and shock.
disease_term:
  term:
    id: MONDO:0005502
    label: dengue disease
  preferred_term: dengue disease
parents:
- Arbovirus Infection
- Neglected tropical disease
infectious_agent:
- name: Dengue virus
  description: Dengue virus comprises four antigenically distinct serotypes (DENV-1 through DENV-4); infection with one serotype confers lifelong homotypic immunity but only short-term cross-protection against the others.
  infectious_agent_term:
    preferred_term: Dengue virus
    term:
      id: NCBITaxon:12637
      label: Dengue virus
  evidence:
  - reference: PMID:34171205
    reference_title: "Dengue virus: epidemiology, biology, and disease aetiology."
    supports: SUPPORT
    snippet: Dengue is a vector-borne viral disease caused by the flavivirus dengue virus (DENV).
    explanation: The review identifies dengue virus as the causative flavivirus.
  - reference: PMID:34171205
    reference_title: "Dengue virus: epidemiology, biology, and disease aetiology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It has four antigenically distinct serotypes, DENV-1 to DENV-4, with different genotypes"
    explanation: Establishes the four antigenically distinct DENV serotypes.
  - reference: PMID:23817881
    reference_title: "Dengue infections."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Infection with any one of the viruses is thought to provide lifetime immunity to future infections from the same virus but only short-term cross-immunity to the other types, leading to the possibility of secondary infections."
    explanation: Documents lifelong homotypic immunity versus short-term heterotypic cross-immunity across the four serotypes.
agent_life_cycle:
  description: Dengue virus cycles between humans and Aedes mosquito vectors.
  hosts:
  - preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
    role: definitive host
  - preferred_term: Aedes aegypti
    term:
      id: NCBITaxon:7159
      label: Aedes aegypti
    role: vector
  - preferred_term: Aedes albopictus
    term:
      id: NCBITaxon:7160
      label: Aedes albopictus
    role: vector
transmission:
- name: Aedes mosquito transmission
  description: Aedes aegypti and Aedes albopictus transmit dengue virus to humans.
  evidence:
  - reference: PMID:23817881
    reference_title: "Dengue infections."
    supports: SUPPORT
    snippet: It is usually transmitted to humans through the bite of an infected Aedes aegypti or Aedes albopictus mosquito.
    explanation: The abstract specifies Aedes aegypti and Aedes albopictus as vectors.
pathophysiology:
- name: Antibody-Dependent Enhancement in Secondary Heterotypic Infection
  description: Secondary infection with a heterotypic dengue virus serotype can enhance disease severity through antibody-dependent enhancement, in which non-neutralizing antibodies from the primary infection promote increased viral uptake and immune dysregulation.
  evidence:
  - reference: PMID:34171205
    reference_title: "Dengue virus: epidemiology, biology, and disease aetiology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the severity of the disease is enhanced via heterotypic infection by various serotypes as well as antibody-dependent enhancement (ADE)"
    explanation: Review states heterotypic serotype infection and ADE enhance dengue disease severity.
  - reference: PMID:32265181
    reference_title: "Dengue hemorrhagic fever - A systemic literature review of current perspectives on pathogenesis, prevention and control."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "antibody-dependent enhancement, cytokine dysregulation and variation of lipid profiles are correlated with DHF occurrence"
    explanation: Review correlates antibody-dependent enhancement with DHF occurrence.
  downstream:
  - target: Plasma Leakage
    description: ADE-driven immune activation and cytokine dysregulation contribute to the vascular permeability underlying severe-dengue plasma leakage.
- name: Natural Killer Cell-Mediated Antibody-Dependent Cellular Cytotoxicity
  biological_scale: CELLULAR
  description: >-
    IgG antibodies (particularly IgG1) bound to dengue-infected cells engage
    Fcγ receptor IIIa (CD16a) on natural killer cells, triggering release of
    cytolytic molecules. This results in killing of DENV-infected cells, a
    protective effector function correlating with lower viremia in secondary
    infections.
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: antibody-dependent cellular cytotoxicity
    term:
      id: GO:0001788
      label: antibody-dependent cellular cytotoxicity
  - preferred_term: natural killer cell mediated cytotoxicity
    term:
      id: GO:0042267
      label: natural killer cell mediated cytotoxicity
  notes: >-
    The cited review limits how much weight the cohort item below can carry:
    direct evidence for ADCC in dengue comes mainly from in vitro work plus one
    early paediatric study, so the human data are an association with viraemia
    rather than a demonstration of NK-mediated killing in patients.
  evidence:
  - reference: PMID:42773233
    reference_title: "Functional antibody responses and protection against symptomatic dengue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "ADCC, where IgG antibodies bind viral antigens on DENV-infected cells and trigger killing of infected cells by natural killer cells through engagement of FcγRIIIa (CD16a)"
    explanation: Grounds the effector cell and the FcγRIIIa/CD16a receptor this node names; the review's synthesis of experimental work it did not perform.
  - reference: PMID:42773233
    reference_title: "Functional antibody responses and protection against symptomatic dengue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "This prospective study reported that high levels of preexisting anti-DENV IgG1 were associated with ADCC, which correlated with lower plasma viraemia during secondary DENV infections"
    explanation: Prospective cohort in which ADCC activity correlates with reduced viraemia; the quote reports an association and does not itself identify the effector cell.
  - reference: PMID:42773233
    reference_title: "Functional antibody responses and protection against symptomatic dengue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "direct evidence for ADCC in dengue comes primarily from in vitro experimental studies and an early paediatric study conducted in Thailand"
    explanation: Records the evidence base behind this node, bounding how far the human cohort association can be read as a mechanism in patients.
- name: Monocyte-Dependent Antibody-Dependent Cellular Phagocytosis
  biological_scale: CELLULAR
  description: >-
    Antibodies opsonize dengue virions and infected cells, promoting their
    uptake and clearance by Fc receptor-expressing monocytes and macrophages.
    ADCP targets both structural (prM, E) and non-structural (NS1) proteins.
    Phagocytic uptake did not result in accumulation of DENV genomic material
    within monocytes, suggesting it does not drive productive infection within
    phagocytes.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: Fc-gamma receptor signaling pathway involved in phagocytosis
    term:
      id: GO:0038096
      label: Fc-gamma receptor signaling pathway involved in phagocytosis
  evidence:
  - reference: PMID:42773233
    reference_title: "Functional antibody responses and protection against symptomatic dengue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "ADCP involves the opsonisation of virions or infected cells with antibodies, usually IgG, leading to their uptake and clearance by Fcγ receptor-expressing phagocytes such as monocytes. Studies have reported that antibodies that promote ADCP can target both structural and non-structural proteins of DENV."
    explanation: Review's synthesis of cell-culture work describing the phagocytic effector route and the breadth of antigens that engage it.
  - reference: PMID:42773233
    reference_title: "Functional antibody responses and protection against symptomatic dengue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Monoclonal antibodies targeting prM and envelope epitopes promoted ADCP of DENV-infected cells by peripheral blood mononuclear cells"
    explanation: Grounds the structural-protein half of this node's antigen claim (prM and E).
  - reference: PMID:42773233
    reference_title: "Functional antibody responses and protection against symptomatic dengue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Using recombinant monoclonal IgG and IgA antibodies against NS1, the authors demonstrated that these antibodies can mediate ADCP through engagement of FcγRI (CD64) and FcαRI (CD89)"
    explanation: Grounds the non-structural (NS1) half of the antigen claim, and names the Fc receptors through which phagocytosis proceeds.
  - reference: PMID:42773233
    reference_title: "Functional antibody responses and protection against symptomatic dengue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "DENV genomic material did not accumulate within monocytes, suggesting that phagocytic uptake did not result in productive infection"
    explanation: Grounds this node's claim that phagocytic uptake does not drive productive infection within monocytes; the source hedges the inference with "suggesting", which the description preserves.
- name: Complement-Mediated Antibody-Dependent Virolysis
  biological_scale: CELLULAR
  description: >-
    Antibodies bound to dengue virions activate the classical complement cascade
    via C1q recruitment, depositing complement components on virions and infected
    cells. This leads to lysis of both free virions and infected cells. ADCD
    correlates with asymptomatic dengue outcomes.
  biological_processes:
  - preferred_term: complement activation, classical pathway
    term:
      id: GO:0006958
      label: complement activation, classical pathway
  - preferred_term: complement-dependent cytotoxicity
    term:
      id: GO:0097278
      label: complement-dependent cytotoxicity
  notes: >-
    This node is antibody-dependent complement activity acting protectively on
    virions and infected cells. It is a different claim from Complement Cascade
    Dysregulation, which carries a transcriptional complement signature in severe
    disease; the two are not alternative readings of one observation.
  evidence:
  - reference: PMID:42773233
    reference_title: "Functional antibody responses and protection against symptomatic dengue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "higher ADCD activities against virions and infected cells were observed in children with inapparent infection compared with symptomatic infection, suggesting a protective role in the ADCD pathway"
    explanation: Clinical observation showing complement-dependent functions correlate with asymptomatic outcomes.
  - reference: PMID:42773233
    reference_title: "Functional antibody responses and protection against symptomatic dengue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "deposition of complement components (C1q) on virions or infected cells, leading to virolysis or complement-mediated lysis of infected cells"
    explanation: Grounds the C1q deposition and lysis steps this node describes; the source stops here and does not describe a membrane attack complex in dengue.
- name: IgA-Mediated Neutralization and Blockade of Antibody-Dependent Enhancement
  biological_scale: CELLULAR
  description: >-
    Dengue-specific IgA antibodies provide protection through direct neutralization
    and blockade of IgG-mediated antibody-dependent enhancement. The absence of
    enhanced inflammation is reported for human macrophage cultures exposed to
    IgA-DENV complexes, and does not extend to IgA responses generally: anti-NS1 IgA
    raised by prior Zika infection is associated with increased risk of severe
    DENV-2 disease through neutrophil Fc-alpha receptor engagement.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: immunoglobulin mediated immune response
    term:
      id: GO:0016064
      label: immunoglobulin mediated immune response
  notes: >-
    The relationship to Antibody-Dependent Enhancement in Secondary Heterotypic
    Infection is deliberately not drawn as a causal edge: the claim is that IgA
    blocks that mechanism, and CausalEdge has no inhibitory predicate, so an edge
    would assert the opposite of what the evidence says.
  evidence:
  - reference: PMID:42773233
    reference_title: "Functional antibody responses and protection against symptomatic dengue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "DENV-specific IgA can display neutralising function and block IgG-mediated ADE"
    explanation: Review's synthesis of cell-culture work establishing the two protective IgA functions this node asserts.
  - reference: PMID:42773233
    reference_title: "Functional antibody responses and protection against symptomatic dengue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "In human macrophage cultures, IgA-DENV complexes did not induce ADE or enhance inflammation, which otherwise may predispose to severe dengue"
    explanation: The system in which the absence of enhancement was shown, which is why this node's description names the culture rather than IgA responses in general.
  - reference: PMID:42773233
    reference_title: "Functional antibody responses and protection against symptomatic dengue."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "It was demonstrated that IgA antibodies, specifically anti-NS1 IgA induced after primary Zika virus infection, are associated with increased risk of severe DENV-2 infection"
    explanation: The same review documents a pathogenic IgA route, so it contradicts any general reading of this node as IgA being uniformly protective; it bounds the claim rather than removing it.
- name: NS1-Induced Endothelial Glycocalyx Degradation
  description: >-
    Secreted dengue NS1 acts directly on vascular endothelium: it induces
    sialidase and heparanase expression and activates cathepsin L, which
    together strip sialic acid and shed heparan sulfate proteoglycans from the
    endothelial glycocalyx layer. Loss of that layer is an endothelial
    cell-intrinsic route to hyperpermeability, separate from the antibody- and
    cytokine-mediated arm above.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  evidence:
  - reference: PMID:27416066
    reference_title: "Dengue Virus NS1 Disrupts the Endothelial Glycocalyx, Leading to Hyperpermeability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we demonstrate that DENV NS1 disrupts the EGL on human pulmonary
      microvascular endothelial cells, inducing degradation of sialic acid and
      shedding of heparan sulfate proteoglycans.
    explanation: Demonstrates the glycocalyx degradation this node asserts, on human endothelial cells.
  - reference: PMID:27416066
    reference_title: "Dengue Virus NS1 Disrupts the Endothelial Glycocalyx, Leading to Hyperpermeability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This effect is mediated by NS1-induced expression of sialidases and
      heparanase, respectively.
    explanation: Identifies the sialidase and heparanase route named in this node's description.
  downstream:
  - target: Plasma Leakage
    causal_link_type: DIRECT
    description: >-
      Stripping the endothelial glycocalyx removes a principal regulator of
      endothelial barrier function, and the resulting hyperpermeability is the
      cell-intrinsic mechanism of plasma leakage.
    evidence:
    - reference: PMID:27416066
      reference_title: "Dengue Virus NS1 Disrupts the Endothelial Glycocalyx, Leading to Hyperpermeability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Specific inhibitors of sialidases, heparanase, and cathepsin L prevent
        DENV NS1-induced EGL disruption and endothelial hyperpermeability.
      explanation: >-
        Blocking the degradation blocks the hyperpermeability, which is the
        interventional form of the causal claim this edge makes.
- name: Plasma Leakage
  conforms_to: viral_hemorrhagic_fever_syndrome#Increased Vascular Permeability
  description: >-
    Increased vascular permeability allows plasma to escape the intravascular
    compartment into the pleural and peritoneal spaces, with hemoconcentration.
    This is the pathophysiological hallmark that separates dengue hemorrhagic
    fever from uncomplicated dengue fever.
  evidence:
  - reference: PMID:32265181
    reference_title: "Dengue hemorrhagic fever - A systemic literature review of current perspectives on pathogenesis, prevention and control."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Plasma leakages is the main pathophysiological hallmark that distinguishes DHF from DF.
    explanation: Identifies plasma leakage as the defining mechanism of the severe form.
  downstream:
  - target: Hypovolemic Shock
    causal_link_type: DIRECT
    description: >-
      When leakage is severe enough, the loss of circulating volume produces
      hypovolemic shock. Splitting this from the leakage node matters
      therapeutically: fluid resuscitation acts on the volume loss, not on the
      permeability that caused it.
    evidence:
    - reference: PMID:32265181
      reference_title: "Dengue hemorrhagic fever - A systemic literature review of current perspectives on pathogenesis, prevention and control."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Severe plasma leakage can result in hypovolemic shock.
      explanation: States the leakage-to-shock progression this edge asserts.
- name: Hypovolemic Shock
  description: >-
    Loss of intravascular volume to the extravascular space produces circulatory
    failure. This is the node fluid resuscitation acts on, and the mechanism
    behind the dengue shock syndrome presentation.
  evidence:
  - reference: PMID:16135832
    reference_title: Comparison of three fluid solutions for resuscitation in dengue shock syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Dengue shock syndrome is characterized by severe vascular leakage and disordered hemostasis and progresses to death in 1 to 5 percent of cases.
    explanation: Characterizes the shock state and its mortality.
  downstream:
  - target: Dengue Shock Syndrome
    causal_link_type: DIRECT
    description: >-
      Hypovolemic shock arising from dengue plasma leakage is the clinical
      presentation named dengue shock syndrome.
    evidence:
    - reference: PMID:16135832
      reference_title: Comparison of three fluid solutions for resuscitation in dengue shock syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Dengue shock syndrome is characterized by severe vascular leakage and disordered hemostasis and progresses to death in 1 to 5 percent of cases.
      explanation: Equates the syndrome with the severe vascular-leakage shock state.
- name: Platelet Activation and Accelerated Platelet Clearance
  description: >-
    Circulating platelets carry DENV genome and become activated, acquiring
    surface complement C3 and IgG and being phagocytosed by monocytes. Platelet
    counts fall around day 4 of fever and recover from day 6 to day 10, tracking
    the activation markers.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:28139770
    reference_title: Platelet activation determines the severity of thrombocytopenia in dengue infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we described a direct correlation between activation and depletion of
      platelets in patients
    explanation: Establishes the activation-to-depletion relationship in dengue patients.
  downstream:
  - target: Thrombocytopenia
    causal_link_type: DIRECT
    description: >-
      Activated platelets are cleared faster than they are replaced, which is
      what the falling platelet count measures.
    evidence:
    - reference: PMID:28139770
      reference_title: Platelet activation determines the severity of thrombocytopenia in dengue infection.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These observations collectively suggest that platelet activation status
        is an important determinant of thrombocytopenia in dengue infections.
      explanation: States platelet activation as a determinant of the thrombocytopenia this edge targets.
  - target: Hemorrhagic Manifestations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Platelet depletion contributes to the bleeding tendency, alongside the
      disordered hemostasis reported in severe dengue. The intermediates are not
      resolved here, so the link is not typed as direct.
    evidence:
    - reference: PMID:28139770
      reference_title: Platelet activation determines the severity of thrombocytopenia in dengue infection.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Studies suggest that the low platelet count is one of the major causes of bleeding in these patients.
      explanation: >-
        Names the low platelet count as a major cause of bleeding, which is the
        specific claim this edge makes. The source says "studies suggest" and
        does not resolve the intermediates, so the edge stays typed as having
        unknown intermediates.
- name: Complement Cascade Dysregulation
  description: >-
    Transcriptional signature of complement dysregulation in pediatric dengue:
    classical and lectin pathway components are upregulated during primary
    infection with concurrent downregulation of several complement regulators
    (FDR-significant). The primary-versus-secondary comparison shows a nominal
    trend toward the reciprocal pattern (C1QA/C1QC/C2/C4b down, CFI/C4BP/MBL2/CFP up),
    which the authors interpret as a transition from activation to regulation in
    secondary infection, though this comparison did not reach FDR significance.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: complement activation
    term:
      id: GO:0006956
      label: complement activation
    modifier: INCREASED
  notes: >-
    The INCREASED modifier reflects the direction of differential *gene
    expression* in PBMCs, not measured complement pathway activity. The authors
    are explicit about this limitation ("We use the term 'activation' here to
    describe the direction of differential gene expression rather than direct
    biochemical evidence of complement cascade activity"), and the cohort is
    small (n = 3 per arm) with no functional validation. The primary-versus-secondary comparison in the second evidence item is based on nominal expression trends rather than FDR-significant differential expression: "after correction for multiple testing (FDR < 0.05, |log₂FC | ≥ 2), none of the complement-pathway genes examined showed statistical significance in the direct primary-versus-secondary comparison." See discussion
    `gap_dengue_pbmc_transcriptomic_signatures_functional_validation`.
  evidence:
  - reference: PMID:42603814
    reference_title: "Bulk transcriptomics of peripheral blood mononuclear cells delineates systems-level immune dysregulation in pediatric dengue infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiple classical and lectin pathway genes were upregulated in the primary dengue cohort, including MBL2, C1QA, C1QB, C1QC, C2, and C9 (Fig. 3). In contrast, several complement regulatory factors were downregulated in the primary dengue cohort, including CD93, properdin (CFP), CR1, SERPING, C4BPA, C4BPB, and CFD"
    explanation: PBMC transcriptomics from a WHO-classified pediatric dengue cohort shows coordinated upregulation of classical and lectin pathway transcripts with downregulation of regulator transcripts in primary infection.
  - reference: PMID:42603814
    reference_title: "Bulk transcriptomics of peripheral blood mononuclear cells delineates systems-level immune dysregulation in pediatric dengue infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further analysis of the primary vs secondary dengue cohort data revealed a widespread downregulation of C1QA, C1QC, C2, and C4b accompanied by upregulation of CFI, C4BP, MBL2, and CFP, which suggests a transition from activation to regulation"
    explanation: PARTIAL rather than SUPPORT - the authors explicitly note that this primary-versus-secondary comparison is based on nominal expression trends rather than FDR-significant differential expression, as none of the complement genes met the FDR < 0.05 threshold in the direct comparison.
  downstream:
  - target: Plasma Leakage
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Excessive or unbalanced complement activation is proposed to increase
      vascular permeability and drive the plasma leakage that defines severe
      dengue. The intermediates linking complement activation products to
      endothelial barrier failure are not established in this cohort.
    evidence:
    - reference: PMID:42603814
      reference_title: "Bulk transcriptomics of peripheral blood mononuclear cells delineates systems-level immune dysregulation in pediatric dengue infection."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Complement activation in dengue is reportedly a double-edged sword, as even though it aids in viral neutralization, inasmuch as excessive or unbalanced activation can contribute to vascular permeability, plasma leakage, which are pathognomonic hallmarks of severe dengue"
      explanation: PARTIAL rather than SUPPORT - this is the discussion-section synthesis of prior human dengue literature by the same authors, not a result of their own transcriptomic study, which did not measure vascular permeability.
- name: Macrophage-Mediated Innate Immune Activation
  description: >-
    Transcriptional signature of macrophage activation in both primary and
    secondary pediatric dengue, marked by elevated expression of
    macrophage-associated markers (ITGB2, SPP1, KLF6) and tissue-remodelling
    genes, with concurrent downregulation of the pro-inflammatory mediators
    S100A8 and BATF that the authors read as feedback restraint.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: macrophage activation
    term:
      id: GO:0042116
      label: macrophage activation
    modifier: INCREASED
  notes: >-
    The INCREASED modifier reflects differential expression of
    macrophage-associated transcripts in bulk PBMCs, not a measured macrophage
    activation state; the authors call the monocyte-macrophage arm "suggestive
    ... pending functional confirmation". See discussion
    `gap_dengue_pbmc_transcriptomic_signatures_functional_validation`.
  evidence:
  - reference: PMID:42603814
    reference_title: "Bulk transcriptomics of peripheral blood mononuclear cells delineates systems-level immune dysregulation in pediatric dengue infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The upregulation of macrophage-associated markers (ITGb2, SPP1, and KLF6) across both primary as well as secondary dengue affirms robust macrophage activation and tissue remodelling. The downregulation of S100A8 and BATF appears to represent feedback restrain exaggerated inflammation.
    explanation: PBMC transcriptomics from a pediatric dengue cohort shows coordinated upregulation of macrophage-associated transcripts alongside downregulation of two pro-inflammatory mediators.
- name: Immune Checkpoint-Mediated T Cell Exhaustion in Secondary Dengue
  description: >-
    Transcriptional signature of immune-checkpoint upregulation (PDCD1/PD-1,
    LAG3, TIGIT, CD96, VSIG4) in pediatric dengue, markedly higher in secondary
    than in primary infection, which the authors interpret as immune exhaustion
    of NK, MAIT and T cells restricting antiviral effector function.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  - preferred_term: mucosal-associated invariant T (MAIT) cell
    term:
      id: CL:0000940
      label: mucosal-associated invariant T cell
  biological_processes:
  - preferred_term: checkpoint-mediated restraint of T cell activation
    term:
      id: GO:0050868
      label: negative regulation of T cell activation
    modifier: INCREASED
  notes: >-
    The INCREASED modifier reflects upregulated checkpoint-molecule transcripts
    in bulk PBMCs; no functional exhaustion assay (cytokine production,
    proliferation, cytotoxicity) was performed, and the authors describe the
    signatures as preliminary.

    The source is internally inconsistent on directionality for three of the
    five genes named in the quoted snippet. The Results section reports that in
    secondary dengue "immune checkpoints associated genes VSIG4, PDCD1, ICOS,
    and CD274 were upregulated whereas LAG3, BTLA, TIGIT, and CD96 exhibited
    downregulation", while the Discussion sentence quoted as evidence here
    places LAG3, TIGIT and CD96 among the upregulated set. The PDCD1/VSIG4 arm
    is consistent across both sections; LAG3, TIGIT and CD96 should be treated
    as unresolved in this source until a larger cohort settles them.

    See discussion
    `gap_dengue_pbmc_transcriptomic_signatures_functional_validation`.
  evidence:
  - reference: PMID:42603814
    reference_title: "Bulk transcriptomics of peripheral blood mononuclear cells delineates systems-level immune dysregulation in pediatric dengue infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Immune checkpoint, including PDCD1, LAG3, TIGIT, CD96, and VSIG4, were upregulated in both primary and secondary pediatric dengue, with markedly higher expressions in the secondary cohort. This enhanced checkpoint activity aligns with the immune exhaustion observed in NK cells, MAIT cells, and T cells, which restrict antiviral effector function.
    explanation: PBMC transcriptomics shows checkpoint-molecule transcripts upregulated in both cohorts and markedly higher in secondary infection, the study's most consistent primary-versus-secondary difference.
phenotypes:
- name: Fever
  category: Systemic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:34171205
    reference_title: "Dengue virus: epidemiology, biology, and disease aetiology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical symptoms of dengue range from mild fever to severe dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), with thrombocytopenia, leucopenia, and increased vascular permeability."
    explanation: The review lists fever as the defining clinical symptom across the dengue disease spectrum.
- name: Skin rash
  category: Dermatologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Skin rash
    term:
      id: HP:0000988
      label: Skin rash
  evidence:
  - reference: PMID:39773842
    reference_title: "Dermatological manifestations during Dengue, Chikungunya, and Zika infections."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In Dengue, distinctive rashes like the 'islands of white in a sea of red' and hemorrhagic skin manifestations have been key diagnostic features."
    explanation: The dermatology review identifies the characteristic dengue rash ("islands of white in a sea of red") as a key diagnostic feature.
- name: Thrombocytopenia
  category: Hematologic
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:34171205
    reference_title: "Dengue virus: epidemiology, biology, and disease aetiology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical symptoms of dengue range from mild fever to severe dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), with thrombocytopenia, leucopenia, and increased vascular permeability."
    explanation: The review lists thrombocytopenia as part of the clinical symptom spectrum of dengue, including severe forms (DHF/DSS).
- name: Hemorrhagic Manifestations
  category: Hematologic
  description: >-
    Bleeding in dengue ranges from petechiae and other hemorrhagic skin lesions
    to mucosal and gastrointestinal bleeding, and is the manifestation the name
    dengue hemorrhagic fever refers to.
  phenotype_term:
    preferred_term: Hemorrhagic manifestations
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:39773842
    reference_title: "Dermatological manifestations during Dengue, Chikungunya, and Zika infections."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In Dengue, distinctive rashes like the 'islands of white in a sea of red'
      and hemorrhagic skin manifestations have been key diagnostic features.
    explanation: Names hemorrhagic skin manifestations as a diagnostic feature of dengue.
  - reference: PMID:16135832
    reference_title: Comparison of three fluid solutions for resuscitation in dengue shock syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Dengue shock syndrome is characterized by severe vascular leakage and disordered hemostasis and progresses to death in 1 to 5 percent of cases.
    explanation: Documents disordered hemostasis as a defining feature of the severe form.
- name: Dengue Shock Syndrome
  category: Systemic
  description: The most severe presentation of dengue, characterized by critical plasma leakage progressing to hypovolemic shock.
  phenotype_term:
    preferred_term: Dengue shock syndrome
    term:
      id: HP:0031274
      label: Hypovolemic shock
  evidence:
  - reference: PMID:16135832
    reference_title: "Comparison of three fluid solutions for resuscitation in dengue shock syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dengue shock syndrome is characterized by severe vascular leakage and disordered hemostasis and progresses to death in 1 to 5 percent of cases."
    explanation: Randomized-trial report characterizing dengue shock syndrome as severe vascular leakage with substantial mortality.
treatments:
- name: Intravenous Fluid Resuscitation
  description: Timely intravenous fluid resuscitation is the critical supportive intervention for dengue shock syndrome; WHO management guidelines for fluid choice remain largely empirical.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: fluid therapy
    term:
      id: NCIT:C116537
      label: Fluid Therapy
  target_mechanisms:
  - target: Hypovolemic Shock
    treatment_effect: RESTORES
    description: >-
      Fluid resuscitation restores the intravascular volume lost to vascular
      leakage. It acts on the shock consequence, not on the permeability that
      produced it, which is why it targets this node rather than Plasma Leakage.
    evidence:
    - reference: PMID:16135832
      reference_title: "Comparison of three fluid solutions for resuscitation in dengue shock syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although volume replacement is recognized as the critical therapeutic intervention, World Health Organization management guidelines remain empirical rather than evidence-based."
      explanation: Randomized trial identifies volume replacement as the critical intervention for dengue shock syndrome.
  evidence:
  - reference: PMID:16135832
    reference_title: "Comparison of three fluid solutions for resuscitation in dengue shock syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although volume replacement is recognized as the critical therapeutic intervention, World Health Organization management guidelines remain empirical rather than evidence-based."
    explanation: Randomized trial identifies volume replacement as the critical intervention for dengue shock syndrome.
- name: Tetravalent Live-Attenuated Dengue Vaccination (TAK-003 / CYD-TDV)
  description: >-
    Active immunization with tetravalent live-attenuated dengue vaccines — the
    DENV-2-backboned TAK-003 (Qdenga) or the yellow fever 17D-backboned chimeric
    CYD-TDV (Dengvaxia) — elicits neutralizing antibodies against all four DENV
    serotypes and, for TAK-003, non-structural protein (NS1) humoral and cellular
    immunity that limits viremia and prevents severe endothelial glycocalyx
    disruption. Clinical deployment is critically modified by baseline dengue
    serostatus: CYD-TDV lacks DENV NS1 antigens and sensitized baseline-seronegative
    vaccinees to antibody-dependent enhancement and increased hospitalization risk
    upon primary wild-type infection, restricting its indication to laboratory-confirmed
    seropositive individuals, whereas TAK-003 demonstrated 4.5-year efficacy and
    safety against all four serotypes in baseline-seropositive individuals and
    against DENV-1 and DENV-2 in baseline-seronegative individuals.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: Vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  target_mechanisms:
  - target: IgA-Mediated Neutralization and Blockade of Antibody-Dependent Enhancement
    treatment_effect: ACTIVATES
    description: >-
      Tetravalent vaccination aims to induce balanced neutralizing antibodies across
      all four dengue serotypes so that virions are neutralized before subneutralizing
      IgG complexes can engage Fc-gamma receptors to drive antibody-dependent
      enhancement.
    evidence:
    - reference: PMID:29482433
      reference_title: "Safety issues from a Phase 3 clinical trial of a live-attenuated chimeric yellow fever tetravalent dengue vaccine."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "There is general agreement that DENV vaccines should ideally induce protective neutralizing antibodies to each of the four serotypes simultaneously."
      explanation: Establishes the mechanistic rationale that balanced tetravalent neutralizing immunity is required to prevent antibody-dependent enhancement across the four DENV serotypes.
  - target: NS1-Induced Endothelial Glycocalyx Degradation
    treatment_effect: INHIBITS
    description: >-
      By suppressing dengue viral replication and, in DENV-backboned vaccines such
      as TAK-003, priming anti-NS1 immunity, vaccination reduces circulating DENV
      NS1 antigen levels and downstream endothelial glycocalyx degradation and
      hospitalized plasma-leakage disease.
    evidence:
    - reference: PMID:38245116
      reference_title: "Long-term efficacy and safety of a tetravalent dengue vaccine (TAK-003): 4·5-year results from a phase 3, randomised, double-blind, placebo-controlled trial."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cumulative vaccine efficacy was 61·2% (95% CI 56·0-65·8) against virologically confirmed dengue and 84·1% (77·8-88·6) against hospitalised virologically confirmed dengue; corresponding efficacies were 53·5% (41·6-62·9) and 79·3% (63·5-88·2) in baseline seronegative participants (safety set)."
      explanation: Phase 3 4.5-year trial data showing 84.1% efficacy against hospitalized virologically confirmed dengue.
  effect_modifiers:
  - effect_modifier_type: BIOMARKER
    stratum: Baseline dengue-seronegative individuals (no prior DENV infection)
    comparator_stratum: Baseline dengue-seropositive individuals (prior DENV infection)
    modified_outcome: Risk of hospitalized virologically confirmed dengue and serotype breadth of vaccine efficacy
    effect_in_stratum: OPPOSITE_EFFECT
    description: >-
      In baseline-seronegative children, the chimeric YF-17D/DENV vaccine CYD-TDV
      acted as a silent primary sensitization that predisposed recipients to
      vaccine-enhanced hospitalized dengue upon subsequent wild-type DENV infection,
      restricting CYD-TDV to individuals with prior dengue infection. In contrast,
      TAK-003 (built on an attenuated DENV-2 backbone retaining DENV NS1) showed no
      increased hospitalization risk in seronegative recipients over 4.5 years and
      protected baseline-seropositive individuals against all four serotypes and
      baseline-seronegative individuals against DENV-1 and DENV-2, but did not show
      efficacy against DENV-3 in baseline-seronegative individuals.
    evidence:
    - reference: PMID:29482433
      reference_title: "Safety issues from a Phase 3 clinical trial of a live-attenuated chimeric yellow fever tetravalent dengue vaccine."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This surmise was validated recently when the manufacturer reported that dengue NS1 IgG antibodies were absent in sera from hospitalized vaccinated children, an observation consistent with their having received Dengvaxia when seronegative."
      explanation: Demonstrates that breakthrough dengue hospitalizations after CYD-TDV occurred in individuals who were dengue-seronegative (lacking anti-NS1 IgG) at vaccination.
    - reference: PMID:38245116
      reference_title: "Long-term efficacy and safety of a tetravalent dengue vaccine (TAK-003): 4·5-year results from a phase 3, randomised, double-blind, placebo-controlled trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In an exploratory analysis, vaccine efficacy was shown against all four serotypes in baseline seropositive participants. In baseline seronegative participants, vaccine efficacy was shown against DENV-1 and DENV-2 but was not observed against DENV-3 and low incidence precluded evaluation against DENV-4."
      explanation: Establishes serotype- and serostatus-dependent efficacy of TAK-003 at 4.5 years in the phase 3 trial.
  evidence:
  - reference: PMID:38245116
    reference_title: "Long-term efficacy and safety of a tetravalent dengue vaccine (TAK-003): 4·5-year results from a phase 3, randomised, double-blind, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TAK-003 demonstrated long-term efficacy and safety against all four DENV serotypes in previously exposed individuals and against DENV-1 and DENV-2 in dengue-naive individuals."
    explanation: Phase 3 randomized trial demonstrating 4.5-year efficacy and safety of tetravalent dengue vaccine TAK-003.
  - reference: PMID:29482433
    reference_title: "Safety issues from a Phase 3 clinical trial of a live-attenuated chimeric yellow fever tetravalent dengue vaccine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In response to the recognized vulnerability of seronegatives, on 29 November 2017, Sanofi issued a press release stating that “For individuals who have not been previously infected by dengue virus, vaccination should not be recommended.”"
    explanation: Documents the serostatus restriction of first-generation chimeric dengue vaccination (CYD-TDV) due to enhanced disease risk in baseline-seronegative recipients.
diagnosis:
- name: Early virological diagnosis (NS1 antigen and dengue RNA)
  description: >-
    In the first days of illness dengue is confirmed by detecting the virus
    itself: NS1 antigen by immunoassay or viral RNA by RT-PCR. Both are most
    sensitive in the viraemic phase (pooled estimates are for days 0-4 after
    symptom onset), when IgM is often not yet detectable; IgM serology takes
    over from day 5 of illness (see the serology row). The timing rule is the
    reason the tests are not interchangeable: a negative IgM in the first days
    does not exclude dengue.
  measurements:
  - preferred_term: dengue NS1 antigen
    term:
      id: LOINC:91064-6
      label: Dengue virus NS1 Ag [Presence] in Serum or Plasma by Immunoassay
  - preferred_term: dengue virus RNA (RT-PCR)
    term:
      id: LOINC:7855-0
      label: Dengue virus 1+2+3+4 RNA [Presence] in Serum by NAA with probe detection
  notes: >-
    A Monarch KG search found no LOINC Part and no method-less code for dengue
    NS1 antigen or for dengue RNA. NS1 binds the serum-or-plasma presence code by
    immunoassay, the method every NS1 test uses (ELISA and rapid tests alike),
    rather than the rapid-immunoassay or quantitative variants (LOINC:75377-2
    Dengue virus NS1 Ag [Presence] in Serum, Plasma or Blood by Rapid
    immunoassay; LOINC:101206-1 Dengue virus NS1 Ag [Units/volume] in Serum or
    Plasma by Immunoassay). RNA binds the pan-serotype serum presence code;
    every dengue RNA presence code in the KG names an amplification method, and
    the serotype-specific codes would make one test four. No reference_ranges:
    both results are qualitative and the cited sources state no diagnostic
    threshold.
  evidence:
  - reference: PMID:26118588
    reference_title: "Clinical evaluation of dengue RNA, NS1, and IgM for diagnosis of dengue in Southern China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNA and NS1 were most valuable for early diagnosis of dengue, whereas IgM
      was best suited as a supplementary method for patients at day 5 or more
      after illness onset.
    explanation: >-
      Diagnostic evaluation in 294 patients from the 2014 Guangzhou outbreak
      states the timing rule: RNA and NS1 early, IgM from day 5 of illness.
  - reference: PMID:40209729
    reference_title: "Evaluating the performance of common reference laboratory tests for acute dengue diagnosis: a systematic review and meta-analysis of RT-PCR, NS1 ELISA, and IgM ELISA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pooled sensitivities of RT-PCR (0-4 days after symptom onset), NS1 ELISA
      (0-4 days), and IgM ELISA (1-7 days) were 95% (95% credible interval
      77-99), 90% (68-98), and 71% (57-84), respectively.
    explanation: >-
      Meta-analysis of data from 161 articles gives the early-illness accuracy
      of RT-PCR and NS1 ELISA against the lower sensitivity of IgM ELISA in the
      first week.
  - reference: PMID:40209729
    reference_title: "Evaluating the performance of common reference laboratory tests for acute dengue diagnosis: a systematic review and meta-analysis of RT-PCR, NS1 ELISA, and IgM ELISA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IgM ELISA shows poor diagnostic accuracy early in the symptom course. NS1
      ELISA shows similar diagnostic accuracy to RT-PCR
    explanation: >-
      The meta-analysis' interpretation: NS1 antigen and RT-PCR are the
      comparable early tests, and IgM is poor early in illness.
- name: Dengue IgM and IgG serology
  description: >-
    Dengue-specific IgM antibody is the diagnostic test from day 5 of illness
    onward, when it performs better than in the first days. IgG antibody is
    read for the patient's immune status rather than to confirm the current
    episode: a positive IgG rapid test indicates a post-primary (secondary)
    infection, and a negative one on days 3-5 of fever indicates a primary one.
  measurements:
  - preferred_term: dengue IgM antibody
    term:
      id: LOINC:25338-5
      label: Dengue virus IgM Ab [Presence] in Serum
  - preferred_term: dengue IgG antibody
    term:
      id: LOINC:29676-4
      label: Dengue virus IgG Ab [Presence] in Serum
  notes: >-
    Both measurements bind the method-less serum presence code rather than an
    immunoassay-, immunoblot- or rapid-test-specific sibling. No reference_ranges:
    IgM and IgG positivity cut-offs are set by each kit, and the cited sources
    define no disease-owned antibody threshold.
  evidence:
  - reference: PMID:26118588
    reference_title: "Clinical evaluation of dengue RNA, NS1, and IgM for diagnosis of dengue in Southern China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNA had a better performance with 98.1% of sensitivity from day 1 to day 4
      after illness onset. IgM performed better at day 5 or more with 74.0% of
      sensitivity.
    explanation: >-
      Places IgM serology after the first four days of illness, when RNA
      detection is the more sensitive test.
  - reference: PMID:35507552
    reference_title: Combining rapid diagnostic tests to estimate primary and post-primary dengue immune status at the point of care.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, IgG RDT positive results were confirmatory of post-primary
      infections. In contrast, IgG RDT negative results were suggestive of both
      primary and post-primary infections on days 1-2 of fever, yet were
      confirmatory of primary infections on days 3-5 of fever.
    explanation: >-
      Cross-sectional surveys of acute suspected dengue patients in Indonesia,
      Vietnam and the Philippines show what an IgG result says about primary
      versus post-primary infection by day of fever.
datasets:
- accession: geo:GSE178240
  title: A population of CD4+CD8+ double-positive T cells associated with risk of plasma leakage in dengue viral infection
  description: According to the WHO 2009 classification, dengue with warning signs (D+W) is at the risk of developing severe form of dengue disease. One of the most important warning signs is plasma leakage, which is a serious complication associated with higher morbidity and mortality. We report that the frequency of CD4+CD8+ double-positive (DP) T cells is significantly increased in patients at risk of developing plasma leakage. Transcriptomic analysis demonstrated that CD4+CD8+ DP cells were distinct from CD4+ Single Positive (SP) T cells, but co-clustered with CD8+ SP cells indicating a largely similar transcriptional profile.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 414
  publication: PMID:35062294
  notes: Identified by GEO DataSets index search for Dengue (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE297386
  title: Vitamin D Enhances Antiviral Responses in Dengue Virus-Infected Macrophages by Modulating Early-Response Gene Expression
  description: Dengue virus (DENV), the etiological agent of dengue fever, remains a global health concern, leading to severe illness and death in the absence of any definitive cure. Research has shown that vitamin D may reduce DENV replication in vitro and that dengue patients with low or deficient vitamin D levels are at higher risk of severe dengue. Studies indicate that viral replication is inhibited in human monocyte-derived macrophages (MDM) differentiated in the presence of vitamin D (D3MDM), suggesting that vitamin D may prevent DENV entry into host cells.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 24
  publication: PMID:40839599
  notes: Identified by GEO DataSets index search for Dengue (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE28405
  title: Genome-wide gene expression analysis of human whole-blood samples in  in response to dengue disease
  description: We looked at the whole-blood transcriptional profiling on dengue patients sampled within 72h of fever presentation and compared the signatures with autologous samples drawn at defervescence and convalescence and to control patients with fever of other etiology. Our data show that the early response in patients mimics those previously only described in vitro and suggests that this innate immune responses may initiate the later adaptive immune responses.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 119
  publication: PMID:21810247
  notes: Identified by GEO DataSets index search for Dengue (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001002276
  title: GWAS data (Illumina 2.5 M SNPs) in Cuban cohorts of dengue disease
  description: We will have 274 individuals typed for the Illumina Human Omni 2.5 chip. The individuals are from two locations in Cuba (Havana and Guantanamo) and from four phenotype classes (asymptomatic, control dengue fever and dengue hemorrhagic fever).
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:28241052
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Dengue"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001002756
  title: GWAS in a dengue Thai cohort
  description: Around 700,000 SNPs were genotyped in 290 controls, 252 dengue fever patients and 159 dengue shock syndrome patients from Thailand.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Dengue"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS50000001944
  title: Establishment of germline-encoded antibodies during primary dengue infection
  description: This study supports the manuscript “Establishment of germline-encoded antibodies during primary dengue infection” and characterizes longitudinal B cell receptor repertoire dynamics during controlled primary DENV1 infection. Bulk BCR sequencing was performed on whole-blood total RNA from flavivirus-naïve participants in a DENV1 live-virus human challenge study. Samples were collected at days 0, 8, 10, 14, and 28 post-infection, corresponding to pre-infection, early viremic, peak viremic/acute, late viremic/critical-phase, and convalescent timepoints.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Dengue"); description-level mentions were not accepted. EGA study_type: Transcriptome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: metabolomics_workbench:ST002164
  title: TMEM41B and VMP1 modulate cellular lipid and energy metabolism for facilitating Dengue virus infection
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Dengue"). Retrieved 2026-08-02.
- accession: massive:MSV000093299
  title: mitochondrial and dengue virus_2023
  description: Dengue virus non-structural protein 3 inhibits mitochondrial respiration by impairing complex I function
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Dengue"). Retrieved 2026-08-02.
discussions:
- discussion_id: gap_dengue_pbmc_transcriptomic_signatures_functional_validation
  prompt: >-
    Do the complement, macrophage and immune-checkpoint transcriptional
    signatures reported in pediatric dengue PBMCs correspond to actual changes
    in complement pathway activity, macrophage activation state, and lymphocyte
    effector function - and do any of them cause, rather than merely accompany,
    severe dengue?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Complement Cascade Dysregulation
  - pathophysiology#Macrophage-Mediated Innate Immune Activation
  - pathophysiology#Immune Checkpoint-Mediated T Cell Exhaustion in Secondary Dengue
  rationale: >-
    All three nodes rest on a single bulk PBMC RNA-seq study of nine children
    (n = 3 primary, n = 3 secondary, n = 3 healthy controls), with no serotyping
    and no functional assay. The authors twice flag the limits of what the data
    can establish: they state that "activation" denotes the direction of
    differential gene expression rather than biochemical complement activity,
    and the abstract calls the signatures preliminary and in need of systematic
    functional validation. Bulk PBMC expression also confounds cell-composition
    shifts with per-cell state changes, so an apparent macrophage-activation
    signature may partly reflect monocyte frequency. The ModifierEnum values on
    these nodes should therefore be read as transcript-level, and no causal edge
    to disease severity is asserted from them.

    Two further limits are specific to the primary-versus-secondary contrast,
    which is the comparison the secondary-infection arms of these nodes rest on.
    First, none of the complement-pathway genes reached significance in that
    contrast after multiple-testing correction, so the reported "transition from
    activation to regulation" is a nominal trend. Second, the paper's Results
    and Discussion sections disagree on the direction of LAG3, TIGIT and CD96 in
    secondary dengue. Both are recorded in the `notes` of the affected nodes;
    resolving either needs an independent cohort rather than reanalysis of these
    nine samples.
  proposed_experiments:
  - experiment_id: exp_dengue_complement_functional_readout
    name: Functional complement readout paired with the transcriptional signature
    description: >-
      In a larger, serotyped pediatric dengue cohort spanning non-severe and
      severe disease, pair PBMC transcriptomics with plasma complement
      activation-product measurement (C3a, C5a, sC5b-9, Bb) and functional
      pathway assays, sampled longitudinally across the febrile, critical and
      convalescent phases. This tests whether the transcriptional "activation to
      regulation" shift tracks measured complement turnover.
    experiment_type:
      preferred_term: prospective clinical cohort with paired transcriptomic and functional complement assays
    decision_criterion: >-
      Concordance between the direction of complement transcript change and
      measured plasma activation products, and association of the activation
      products with plasma leakage severity.
    supporting_outcome:
    - >-
      Measured complement activation products track the transcriptional
      signature and scale with plasma leakage, converting this node from a
      transcript-level observation into a measured mechanism and grounding its
      edge to plasma leakage.
    refuting_outcome:
    - >-
      Complement activation products are unchanged or discordant with the
      transcript direction, indicating the signature is a bystander readout and
      that the modifier on this node should not be read as pathway activity.
    would_support:
    - pathophysiology#Complement Cascade Dysregulation
    would_refute:
    - pathophysiology#Complement Cascade Dysregulation
  - experiment_id: exp_dengue_checkpoint_exhaustion_functional_assay
    name: Single-cell and functional test of the checkpoint-exhaustion signature
    description: >-
      Apply single-cell RNA-seq with surface-protein profiling to separate
      cell-composition shifts from per-cell state changes, and test exhaustion
      functionally in NK, MAIT and T cells from primary versus secondary
      pediatric dengue - antigen-stimulated cytokine production, proliferation
      and cytotoxicity, with and without PD-1/LAG3/TIGIT blockade ex vivo.
    experiment_type:
      preferred_term: single-cell multi-omic profiling with ex vivo functional lymphocyte assays
    decision_criterion: >-
      Reduced effector function in checkpoint-high lymphocytes from secondary
      dengue, partially restored by checkpoint blockade ex vivo.
    supporting_outcome:
    - >-
      Checkpoint-high NK/MAIT/T cells show measurably impaired effector function
      that is partially reversible, establishing exhaustion rather than
      transcript upregulation alone.
    refuting_outcome:
    - >-
      Effector function is preserved despite checkpoint upregulation, indicating
      transient activation-associated checkpoint expression rather than
      exhaustion, and requiring this node to be reframed.
    would_support:
    - pathophysiology#Immune Checkpoint-Mediated T Cell Exhaustion in Secondary Dengue
    would_refute:
    - pathophysiology#Immune Checkpoint-Mediated T Cell Exhaustion in Secondary Dengue
  evidence:
  - reference: PMID:42603814
    reference_title: "Bulk transcriptomics of peripheral blood mononuclear cells delineates systems-level immune dysregulation in pediatric dengue infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While our initial findings provide early insights into the transcriptional patterns potentially associated with disease outcomes, the dysregulated transcriptomic signatures reported here are preliminary requiring systemic functional validation to determine their biologic role in the immunopathogenesis of pediatric dengue infection"
    explanation: The authors' own statement that the signatures underlying these three nodes are preliminary and require functional validation.
  notes: >-
    Antibody-dependent enhancement (ADE) is the canonical driver of
    secondary-dengue severity and is covered in this entry's deep-research
    artifacts, but is not yet modelled as a pathophysiology node. An ADE node
    would be the natural upstream anchor for these three secondary-infection
    nodes; that is a separate curation increment.
📚

References & Deep Research

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Disorder ▸

Disorder

  • Name: Dengue
  • Category: Infectious Disease
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 11

Key Pathophysiology Nodes

  • Plasma leakage leading to shock in severe dengue
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1016/j.molmed.2024.03.006
  • DOI:10.1017/erm.2024.18
  • DOI:10.1080/22221751.2024.2404159
  • DOI:10.1371/journal.ppat.1012167
  • DOI:10.3390/ijms252111624
  • DOI:10.3390/v16071090
Falcon ▸
Pathophysiology description
Edison Scientific Literature 19 citations 2025-12-15T09:09:44.914475

Pathophysiology description

Dengue results from complex interactions between viral factors (notably secreted nonstructural protein 1, NS1) and host immune responses that collectively produce vascular leak, coagulopathy, and organ dysfunction. In severe disease, vascular permeability is driven by NS1-triggered endothelial glycocalyx degradation, tight-junction alterations, complement activation/modulation, mast cell mediators, and inflammatory lipids and cytokines, superimposed on antibody- and cell-mediated immunopathology during secondary or heterotypic infections. The clinical course typically evolves from a febrile viremic phase (days 1–3/6) to a critical phase with plasma leakage and shock in a subset of patients, followed by a recovery phase if supported appropriately (reviewed in 2024) (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024) (malavige2024molecularmechanismsin pages 1-2, malavige2024molecularmechanismsin pages 14-15, malavige2024molecularmechanismsin pages 5-7).

Key contemporary insights include: (i) NS1 is a major endothelial toxin and immunomodulator that activates TLR4-driven inflammation, cooperates with host proteases (e.g., MMP-9) to disrupt junctions and the glycocalyx, and manipulates complement; (ii) antibody-dependent enhancement (ADE) increases viral uptake via Fcγ receptors and amplifies cytokine production; (iii) DENV NS proteins antagonize type I interferon induction/signaling; (iv) the inflammasome can sense NS1 and contributes to protection; (v) hematologic dysfunction reflects both impaired platelet/megakaryocyte biology and immune-mediated destruction; and (vi) T/NK/Treg cell functional skewing correlates with progression to severe dengue (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024; https://doi.org/10.1371/journal.ppat.1012167, Apr 2024; https://doi.org/10.3390/ijms252111624, Oct 2024; https://doi.org/10.3390/v16071090, Jul 2024) (malavige2024molecularmechanismsin pages 1-2, malavige2024molecularmechanismsin pages 14-15, malavige2024molecularmechanismsin pages 5-7, wong2024theinflammasomepathway pages 17-18, garcia2024exploringthecontrasts pages 2-4, cherie2024immunohaematologicaspectsof pages 13-14, cherie2024immunohaematologicaspectsof pages 11-12).

Mechanism Molecular players (HGNC gene/protein symbols) Cell types (CL IDs/names) Biological processes (GO terms) Cellular components (GO-CC) Anatomy (UBERON) Chemicals (CHEBI) Primary sources (DOI URL, context ID)
NS1-induced endothelial dysfunction and glycocalyx degradation Viral: NS1; Host: TLR4, MMP9, HPSE, sialidases (e.g., NEU1) Endothelial cell (CL:0000115); Monocyte (CL:0000576) Endothelial glycocalyx degradation; increased vascular permeability; inflammatory signaling (e.g., TLR4 pathway) Extracellular region (GO:0005576); plasma membrane (GO:0005886) Blood vessel (UBERON:0001981) Heparan sulfate, HDL (lipoproteins), ROS Malavige & Ogg 2024 (malavige2024molecularmechanismsin pages 1-2); Wong et al. 2024 (wong2024theinflammasomepathway pages 17-18)
Complement activation and modulation by NS1 Viral: NS1; Host: C3, C4A/C4B, C4BP, vitronectin (VTN) Endothelial cell (CL:0000115); Plasma proteins Complement activation (classical and lectin pathways); regulation/inhibition of MAC formation Extracellular region (GO:0005576); blood microparticle Blood vessel (UBERON:0001981); Plasma (UBERON:0001969) Complement components (C3/C4), vitronectin Malavige & Ogg 2024 (malavige2024molecularmechanismsin pages 14-15); Wong et al. 2024 (wong2024theinflammasomepathway pages 17-18); Cherie et al. 2024 (cherie2024immunohaematologicaspectsof pages 11-12)
Antibody-dependent enhancement (FcγR-mediated) and downstream cytokine induction Host: FCGR2A (FcγRIIA), FCGR3A (FcγRIIIA), IgG (antibody Fc) ; signaling: SYK, TBC1D24/SV2B (host factors reported) Monocyte (CL:0000576); Macrophage (CL:0000235); Dendritic cell (CL:0000451); B cell (CL:0000236) FcγR-mediated viral uptake; enhanced viral replication; elevated inflammatory cytokine production (IL-6, IL-10) Endocytic vesicle (GO:0030135); plasma membrane (GO:0005886) Blood / secondary lymphoid tissue (UBERON:0002293) Immune complexes; cytokines (IL-6, IL-10) Malavige & Ogg 2024 (malavige2024molecularmechanismsin pages 5-7); García & De Sanctis 2024 (garcia2024exploringthecontrasts pages 2-4); Wang et al. 2024 (yuya2024progressandchallenges pages 12-12)
Platelet / megakaryocyte dysfunction and thrombocytopenia Platelet proteins: ITGA2B, ITGB3; Host immune: anti-NS1 antibodies (cross-reactive), desialylases, P-selectin (SELP) Platelet (CL:0000182); Megakaryocyte (CL:0000094) Impaired thrombopoiesis; platelet activation/apoptosis; immune-mediated platelet clearance Platelet alpha granule (GO:0031091); plasma membrane Bone marrow (UBERON:0002371); Blood (UBERON:0000178) Platelet-activating factor (PAF); serotonin; sialic acid substrates Cherie et al. 2024 (cherie2024immunohaematologicaspectsof pages 11-12); Malavige & Ogg 2024 (malavige2024molecularmechanismsin pages 5-7)
Innate immune antagonism (IFN pathway suppression by viral NS proteins) Viral: NS2B/NS3, NS4A, NS4B, NS5; Host: STAT2, IRF3, RIG-I (DDX58) Infected epithelial/immune cells: Keratinocyte; Monocyte; Dendritic cell Type I IFN induction and signaling suppression; inhibition of ISG expression; modulation of mitochondrial antiviral signaling Cytosol (GO:0005829); endoplasmic reticulum (GO:0005783); mitochondrion (GO:0005739) Lymphoid organs; infected tissues (varies) Interferons (IFN-α/β) (CHEBI:35352) Malavige & Ogg 2024 (malavige2024molecularmechanismsin pages 1-2); Wang et al. 2024 (yuya2024progressandchallenges pages 12-12)
Inflammasome activation by NS1 Viral: NS1; Host: NLRP3, CASP1, IL1B Macrophage (CL:0000235); Monocyte (CL:0000576) Activation of inflammasome complex; caspase-1 activation; IL-1β release (proinflammatory) Cytosol (GO:0005829); inflammasome complex Blood / infected tissues IL-1β (CHEBI:26412) Wong et al. 2024 (wong2024theinflammasomepathway pages 17-18); Malavige & Ogg 2024 (malavige2024molecularmechanismsin pages 5-7)
Mast cell mediators and vascular leak Mast cell proteases: CMA1 (chymase), TPSAB1 (tryptase); histamine receptors Mast cell (CL:0000095); Endothelial cell (CL:0000115) Mast cell degranulation; release of chymase/tryptase/histamine → increased vascular permeability and vasodilation Secretory granule (GO:0030141); extracellular region Blood vessel (UBERON:0001981); Skin/vascular beds Histamine; leukotrienes; chymase/tryptase substrates Malavige & Ogg 2024 (malavige2024molecularmechanismsin pages 5-7); García & De Sanctis 2024 (garcia2024exploringthecontrasts pages 2-4); Cherie et al. 2024 (cherie2024immunohaematologicaspectsof pages 11-12)
Adaptive immunity bias (Th1/Th2, Treg dysfunction) Host: IFNG, IL4, IL10, CD274 (PD-L1), FOXP3 (Tregs) CD4+ T cell (CL:0000235); CD8+ T cell (CL:0000648); Regulatory T cell (Treg, CL:0000818); NKT cell (CL:0000784) Th1/Th2 polarization; impaired regulatory T cell suppression; skewed helper responses influencing antibody class/glycosylation Immunological synapse (GO:0001772); nucleus (GO:0005634) Secondary lymphoid tissue (UBERON:0000029); blood Cytokines (IFN-γ, IL-4, IL-10) Malavige & Ogg 2024 (malavige2024molecularmechanismsin pages 1-2); Cherie et al. 2024 (cherie2024immunohaematologicaspectsof pages 11-12); Wang et al. 2024 (yuya2024progressandchallenges pages 12-12)

Table: Concise mapping of major dengue pathophysiology mechanisms to molecular players, affected cell types, GO/CC/UBERON/CHEBI terms, and primary recent sources (DOIs) to support ontology-style annotation and knowledgebase curation.

1. Core Pathophysiology

  • Primary mechanisms of vascular leak and shock:
  • NS1-induced endothelial dysfunction: NS1 engages TLR4 on monocytes/macrophages and endothelial cells to induce inflammatory cytokines; activates cathepsin L, sialidases, and heparinase to degrade endothelial sialic acids and the glycocalyx; upregulates PLA2, generating inflammatory lipid mediators; and partners with MMP-9 to reduce ZO-1 and β-catenin at junctions, promoting permeability (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024) (malavige2024molecularmechanismsin pages 5-7). NS1-triggered endothelial dysfunction and glycocalyx disruption are central to severe disease in human-relevant models and can be mitigated by NS1 vaccination or NS1-blocking antibodies (https://doi.org/10.1371/journal.ppat.1012167, Apr 2024) (wong2024theinflammasomepathway pages 17-18).
  • Complement activation/modulation by NS1: NS1 antagonizes complement (e.g., C4), interacts with C4b-binding protein and vitronectin to limit membrane attack complex formation, but contributes to vascular leak through immune complex formation and anaphylatoxin generation in vivo (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024) (malavige2024molecularmechanismsin pages 14-15, malavige2024molecularmechanismsin pages 5-7).
  • Mast cell mediators and lipid signaling: mast cell chymase/tryptase, platelet-activating factor, leukotrienes, and prostaglandins augment permeability and shock; chymase is a predictive biomarker of severe disease (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024; https://doi.org/10.3390/ijms252111624, Oct 2024) (malavige2024molecularmechanismsin pages 5-7, garcia2024exploringthecontrasts pages 2-4).

  • Inflammasome sensing of NS1: human/murine macrophages release IL‑1β in a caspase‑1–dependent manner upon NS1 exposure; NS1-induced inflammasome activation occurs without pyroptotic death and mice lacking caspase‑1/11 are more susceptible to lethal DENV, indicating a protective role (https://doi.org/10.1371/journal.ppat.1012167, Apr 2024) (wong2024theinflammasomepathway pages 17-18).

  • Immune-mediated enhancement (ADE): sub-neutralizing IgG facilitates FcγR-mediated DENV uptake into monocytes/macrophages/DCs, increasing intracellular viral replication and inflammatory cytokines (e.g., IL‑10, IL‑6); outcome depends on antibody specificity, affinity, and concentration (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024; https://doi.org/10.3390/ijms252111624, Oct 2024; animal-model synthesis: https://doi.org/10.1080/22221751.2024.2404159, Sep 2024) (malavige2024molecularmechanismsin pages 5-7, garcia2024exploringthecontrasts pages 2-4, yuya2024progressandchallenges pages 12-12).

  • Innate immune antagonism: DENV NS proteins suppress type I IFN at induction and signaling levels. NS2A/NS3/NS4B inhibit RIG‑I/MAVS signaling and ISG induction; NS5 targets STAT2 to blunt IFN signaling; these activities, together with mitochondrial pathway modulation, facilitate viremia and dissemination (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024) (malavige2024molecularmechanismsin pages 1-2).

2. Key Molecular Players

  • Genes/Proteins (HGNC):
  • Viral: NS1 (DENV NS1), NS2A, NS2B/NS3 (serine protease complex), NS4A, NS4B, NS5 (RdRp/methyltransferase) (malavige2024molecularmechanismsin pages 1-2, malavige2024molecularmechanismsin pages 14-15, malavige2024molecularmechanismsin pages 5-7).
  • Host innate signaling: TLR4 (TLR4), RIG-I (DDX58), IRF3 (IRF3), STAT2 (STAT2) (malavige2024molecularmechanismsin pages 1-2, malavige2024molecularmechanismsin pages 14-15).
  • Endothelial/glycocalyx remodeling: MMP‑9 (MMP9), heparanase (HPSE), sialidases (e.g., NEU1), tight junction protein ZO‑1 (TJP1), β‑catenin (CTNNB1) (malavige2024molecularmechanismsin pages 5-7).
  • Complement: C4A/C4B, C4BP, C3, Vitronectin (VTN) (malavige2024molecularmechanismsin pages 14-15).
  • Inflammasome/cytokines: CASP1, IL1B, IL6, IL10, TNF (wong2024theinflammasomepathway pages 17-18, malavige2024molecularmechanismsin pages 5-7).
  • Fc receptors: FCGR2A (FcγRIIA), FCGR3A (FcγRIIIA) (malavige2024molecularmechanismsin pages 5-7, garcia2024exploringthecontrasts pages 2-4).

  • Hematology/platelets: P‑selectin (SELP), platelet integrins (ITGA2B/ITGB3) (cherie2024immunohaematologicaspectsof pages 11-12).

  • Chemical entities (CHEBI):

  • Platelet-activating factor (PAF), histamine, leukotrienes, prostaglandins; interferon‑α/β; IL‑1β (malavige2024molecularmechanismsin pages 5-7, wong2024theinflammasomepathway pages 17-18).

  • Cell types (CL):

  • Endothelial cell (CL:0000115), monocyte (CL:0000576), macrophage (CL:0000235), dendritic cell (CL:0000451), mast cell (CL:0000095), platelet (CL:0000182), megakaryocyte (CL:0000094), CD4+ and CD8+ T cells (CL:0000235; CL:0000648), Treg (CL:0000818), NK cell (CL:0000623) (malavige2024molecularmechanismsin pages 1-2, malavige2024molecularmechanismsin pages 14-15, malavige2024molecularmechanismsin pages 5-7, wong2024theinflammasomepathway pages 17-18, cherie2024immunohaematologicaspectsof pages 11-12, cherie2024immunohaematologicaspectsof pages 13-14).

  • Anatomical locations (UBERON):

  • Blood vessel (UBERON:0001981), plasma (UBERON:0001969), bone marrow (UBERON:0002371), secondary lymphoid tissue (UBERON:0000029) (malavige2024molecularmechanismsin pages 14-15, cherie2024immunohaematologicaspectsof pages 11-12).

3. Biological Processes (GO terms; disrupted)

  • Endothelial barrier function and vascular permeability; endothelial glycocalyx organization; extracellular matrix disassembly (MMP‑mediated); complement activation (classical/lectin); Fc receptor–mediated endocytosis; type I interferon signaling; inflammasome activation and IL‑1β production; platelet activation and apoptosis; mast cell degranulation; cytokine production (IL‑6, IL‑10, TNF) (malavige2024molecularmechanismsin pages 5-7, malavige2024molecularmechanismsin pages 14-15, wong2024theinflammasomepathway pages 17-18, cherie2024immunohaematologicaspectsof pages 11-12, malavige2024molecularmechanismsin pages 1-2, garcia2024exploringthecontrasts pages 2-4, cherie2024immunohaematologicaspectsof pages 13-14).

4. Cellular Components (GO-CC)

  • Endothelial plasma membrane and tight/adherens junctions; endothelial glycocalyx; extracellular region/plasma; endosomes and FcγR-containing vesicles; mitochondria and ER-derived replication complexes; inflammasome complexes; platelet alpha/dense granules (malavige2024molecularmechanismsin pages 5-7, malavige2024molecularmechanismsin pages 14-15, wong2024theinflammasomepathway pages 17-18, malavige2024molecularmechanismsin pages 1-2, cherie2024immunohaematologicaspectsof pages 11-12).

5. Disease Progression (sequence of events)

  • Early/febrile phase: high viremia with fever, myalgia, headache; NS1 and virions circulate; innate antagonism by NS proteins delays antiviral state (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024) (malavige2024molecularmechanismsin pages 1-2).
  • Critical phase (typically days 3–6): NS1-driven endothelial dysfunction and glycocalyx degradation; complement and mast cell activation; rising inflammatory lipids and cytokines; plasma leakage into pleural/peritoneal spaces; hemoconcentration; shock in severe cases (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024; https://doi.org/10.3390/ijms252111624, Oct 2024) (malavige2024molecularmechanismsin pages 14-15, malavige2024molecularmechanismsin pages 5-7, garcia2024exploringthecontrasts pages 2-4).
  • Recovery phase: reabsorption of extravasated fluid, bradycardia/pruritus common; risk for fluid overload if resuscitation over-continued (review) (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024) (malavige2024molecularmechanismsin pages 1-2).

6. Phenotypic Manifestations (and mechanistic links)

  • Plasma leakage and shock: due to NS1-mediated glycocalyx and junctional disruption, complement anaphylatoxins, mast cell and lipid mediators (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024; https://doi.org/10.1371/journal.ppat.1012167, Apr 2024) (malavige2024molecularmechanismsin pages 5-7, wong2024theinflammasomepathway pages 17-18).
  • Hemorrhage and coagulopathy: platelet activation and apoptosis, NS1–platelet interactions, anti-NS1 cross-reactivity with hemostatic proteins, endothelial activation; disturbances in coagulation/fibrinolysis (https://doi.org/10.3390/v16071090, Jul 2024; https://doi.org/10.1016/j.molmed.2024.03.006, May 2024) (cherie2024immunohaematologicaspectsof pages 11-12, malavige2024molecularmechanismsin pages 5-7).
  • Thrombocytopenia: reduced thrombopoiesis (megakaryocyte dysfunction), increased platelet activation/apoptosis and immune clearance (desialylation, anti-platelet autoantibodies) (https://doi.org/10.3390/v16071090, Jul 2024; https://doi.org/10.1017/erm.2024.18, Oct 2024) (cherie2024immunohaematologicaspectsof pages 11-12, cherie2024immunohaematologicaspectsof pages 13-14).
  • Neurologic and systemic complications: reviews highlight expanding reports of CNS/PNS involvement; systemic cytokine storm contributes to multiorgan dysfunction (https://doi.org/10.3390/ijms252111624, Oct 2024) (garcia2024exploringthecontrasts pages 2-4).

Expert opinions and analysis (authoritative sources)

  • Trends in Molecular Medicine (2024) emphasizes NS1 as a central mediator of vascular leak, interacting with TLR4, complement, lipoproteins, and MMP‑9, with strong translational implications (biomarkers and NS1-targeting) (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024) (malavige2024molecularmechanismsin pages 1-2, malavige2024molecularmechanismsin pages 14-15, malavige2024molecularmechanismsin pages 5-7).
  • PLOS Pathogens (2024) defines NS1 as an inflammasome-activating DAMP in macrophages; genetic ablation of caspase‑1/11 increases susceptibility, suggesting a protective axis that could be harnessed therapeutically (https://doi.org/10.1371/journal.ppat.1012167, Apr 2024) (wong2024theinflammasomepathway pages 17-18).
  • Emerging Microbes & Infections (2024) synthesizes ADE in animal models and reinforces its relevance to vaccine and challenge models, guiding design and interpretation of immune responses in vivo (https://doi.org/10.1080/22221751.2024.2404159, Sep 2024) (yuya2024progressandchallenges pages 12-12).

Current applications and real-world implementations

  • Vaccines: CYD‑TDV (Dengvaxia) and TAK‑003 (Qdenga) are licensed; real-world and trial data emphasize baseline serostatus and balanced immunity to reduce ADE risk; TAK‑003 elicits durable T‑cell responses to NS proteins in children/adolescents (review) (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024) (malavige2024molecularmechanismsin pages 1-2).
  • NS1-targeted strategies: neutralizing/blocking anti‑NS1 antibodies and vaccines mitigate NS1-induced endothelial dysfunction in preclinical models (review and primary) (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024; https://doi.org/10.1371/journal.ppat.1012167, Apr 2024) (malavige2024molecularmechanismsin pages 14-15, wong2024theinflammasomepathway pages 17-18).
  • Biomarkers and supportive care: recognition of critical-phase risk using clinical/lab markers consistent with NS1 and cytokine biology (hemoconcentration, platelet nadir) guides fluid therapy and monitoring (review) (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024) (malavige2024molecularmechanismsin pages 1-2).

Relevant statistics and data (recent)

  • “Half of the global population is at risk,” with a large and rising burden over two decades; severe disease is driven by vascular leakage, organ dysfunction, and bleeding (reviewed 2024) (https://doi.org/10.1016/j.molmed.2024.03.006, May 2024) (malavige2024molecularmechanismsin pages 1-2).
  • Global transmission was reported in all WHO regions in 2023, underscoring expanding geographic risk (https://doi.org/10.3390/ijms252111624, Oct 2024) (garcia2024exploringthecontrasts pages 2-4).

Evidence items (with PMIDs/DOIs, URLs, dates)

  • Malavige GN, Ogg GS. Molecular mechanisms in the pathogenesis of dengue infections. Trends Mol Med. 2024-05. DOI: 10.1016/j.molmed.2024.03.006. URL: https://doi.org/10.1016/j.molmed.2024.03.006 (malavige2024molecularmechanismsin pages 1-2, malavige2024molecularmechanismsin pages 14-15, malavige2024molecularmechanismsin pages 5-7).
  • Wong MP et al. The inflammasome pathway is activated by dengue virus non-structural protein 1 and is protective during dengue virus infection. PLOS Pathog. 2024-04. DOI: 10.1371/journal.ppat.1012167. URL: https://doi.org/10.1371/journal.ppat.1012167 (wong2024theinflammasomepathway pages 17-18).
  • García AH, De Sanctis JB. Exploring the Contrasts and Similarities of Dengue and SARS-CoV-2 Infections. Int J Mol Sci. 2024-10. DOI: 10.3390/ijms252111624. URL: https://doi.org/10.3390/ijms252111624 (garcia2024exploringthecontrasts pages 2-4).
  • Cherie TJJ et al. Immuno-haematologic Aspects of Dengue Infection. Viruses. 2024-07. DOI: 10.3390/v16071090. URL: https://doi.org/10.3390/v16071090 (cherie2024immunohaematologicaspectsof pages 13-14, cherie2024immunohaematologicaspectsof pages 11-12).
  • Wang Y et al. Progress and challenges in development of animal models for dengue virus infection. Emerg Microbes Infect. 2024-09. DOI: 10.1080/22221751.2024.2404159. URL: https://doi.org/10.1080/22221751.2024.2404159 (yuya2024progressandchallenges pages 12-12).

Structured annotations

  • Genes/Proteins (HGNC): NS1 (viral), NS2A, NS2B/NS3, NS4A, NS4B, NS5; TLR4; DDX58 (RIG‑I); IRF3; STAT2; MMP9; HPSE; NEU1; TJP1; CTNNB1; C4A/C4B; C4BP; C3; VTN; CASP1; IL1B; IL6; IL10; TNF; FCGR2A; FCGR3A; SELP; ITGA2B; ITGB3 (malavige2024molecularmechanismsin pages 1-2, malavige2024molecularmechanismsin pages 14-15, malavige2024molecularmechanismsin pages 5-7, wong2024theinflammasomepathway pages 17-18, cherie2024immunohaematologicaspectsof pages 11-12, garcia2024exploringthecontrasts pages 2-4).
  • GO Biological Processes: endothelial glycocalyx organization; regulation of vascular permeability; complement activation (classical pathway); Fc receptor–mediated endocytosis; type I interferon signaling pathway; inflammasome complex assembly; platelet activation; mast cell degranulation; cytokine production involved in immune response (malavige2024molecularmechanismsin pages 5-7, malavige2024molecularmechanismsin pages 14-15, wong2024theinflammasomepathway pages 17-18, malavige2024molecularmechanismsin pages 1-2, cherie2024immunohaematologicaspectsof pages 11-12, garcia2024exploringthecontrasts pages 2-4).
  • GO Cellular Components: plasma membrane; extracellular region; tight junction; adherens junction; endocytic vesicle; mitochondrion; endoplasmic reticulum; inflammasome complex; platelet granule (malavige2024molecularmechanismsin pages 5-7, malavige2024molecularmechanismsin pages 14-15, wong2024theinflammasomepathway pages 17-18, malavige2024molecularmechanismsin pages 1-2, cherie2024immunohaematologicaspectsof pages 11-12).
  • Cell types (CL): endothelial cell (CL:0000115); monocyte (CL:0000576); macrophage (CL:0000235); dendritic cell (CL:0000451); mast cell (CL:0000095); platelet (CL:0000182); megakaryocyte (CL:0000094); CD4+ T cell (CL:0000235); CD8+ T cell (CL:0000648); regulatory T cell (CL:0000818); NK cell (CL:0000623) (malavige2024molecularmechanismsin pages 1-2, malavige2024molecularmechanismsin pages 14-15, malavige2024molecularmechanismsin pages 5-7, wong2024theinflammasomepathway pages 17-18, cherie2024immunohaematologicaspectsof pages 11-12, cherie2024immunohaematologicaspectsof pages 13-14).
  • Anatomy (UBERON): blood vessel (UBERON:0001981); plasma (UBERON:0001969); bone marrow (UBERON:0002371); secondary lymphoid tissue (UBERON:0000029) (malavige2024molecularmechanismsin pages 14-15, cherie2024immunohaematologicaspectsof pages 11-12).
  • Chemical entities (CHEBI): platelet-activating factor; histamine; leukotrienes; prostaglandins; interferon‑α/β; interleukin‑1β (malavige2024molecularmechanismsin pages 5-7, wong2024theinflammasomepathway pages 17-18).

Notes on evidence scope

Where precise 2023–2024 global case numbers are requested, our current evidence includes authoritative statements of global risk and WHO-region transmission in 2023; additional WHO surveillance data would refine counts. Mechanistic sections emphasize 2023–2024 peer‑reviewed reviews and primary studies that directly support NS1-driven vascular injury, ADE, IFN antagonism, inflammasome activation, hematologic dysfunction, and adaptive immune skewing (malavige2024molecularmechanismsin pages 1-2, malavige2024molecularmechanismsin pages 14-15, malavige2024molecularmechanismsin pages 5-7, wong2024theinflammasomepathway pages 17-18, garcia2024exploringthecontrasts pages 2-4, cherie2024immunohaematologicaspectsof pages 11-12, yuya2024progressandchallenges pages 12-12).

References

  1. (malavige2024molecularmechanismsin pages 1-2): Gathsaurie Neelika Malavige and Graham S. Ogg. Molecular mechanisms in the pathogenesis of dengue infections. Trends in Molecular Medicine, 30:484-498, May 2024. URL: https://doi.org/10.1016/j.molmed.2024.03.006, doi:10.1016/j.molmed.2024.03.006. This article has 28 citations and is from a domain leading peer-reviewed journal.

  2. (malavige2024molecularmechanismsin pages 14-15): Gathsaurie Neelika Malavige and Graham S. Ogg. Molecular mechanisms in the pathogenesis of dengue infections. Trends in Molecular Medicine, 30:484-498, May 2024. URL: https://doi.org/10.1016/j.molmed.2024.03.006, doi:10.1016/j.molmed.2024.03.006. This article has 28 citations and is from a domain leading peer-reviewed journal.

  3. (malavige2024molecularmechanismsin pages 5-7): Gathsaurie Neelika Malavige and Graham S. Ogg. Molecular mechanisms in the pathogenesis of dengue infections. Trends in Molecular Medicine, 30:484-498, May 2024. URL: https://doi.org/10.1016/j.molmed.2024.03.006, doi:10.1016/j.molmed.2024.03.006. This article has 28 citations and is from a domain leading peer-reviewed journal.

  4. (wong2024theinflammasomepathway pages 17-18): Marcus P. Wong, Evan Y. W. Juan, Felix Pahmeier, Sai S. Chelluri, Phoebe Wang, Bryan Castillo-Rojas, Sophie F. Blanc, Scott B. Biering, Russell E. Vance, and Eva Harris. The inflammasome pathway is activated by dengue virus non-structural protein 1 and is protective during dengue virus infection. PLOS Pathogens, 20:e1012167, Apr 2024. URL: https://doi.org/10.1371/journal.ppat.1012167, doi:10.1371/journal.ppat.1012167. This article has 11 citations and is from a highest quality peer-reviewed journal.

  5. (garcia2024exploringthecontrasts pages 2-4): Alexis Hipólito García and Juan Bautista De Sanctis. Exploring the contrasts and similarities of dengue and sars-cov-2 infections during the covid-19 era. International Journal of Molecular Sciences, Oct 2024. URL: https://doi.org/10.3390/ijms252111624, doi:10.3390/ijms252111624. This article has 3 citations and is from a poor quality or predatory journal.

  6. (cherie2024immunohaematologicaspectsof pages 13-14): Tan Jiao Jie Cherie, Clarice Shi Hui Choong, Muhammad Bilal Abid, Matthew W. Weber, Eng Soo Yap, Suranjith L. Seneviratne, Visula Abeysuriya, and Sanjay de Mel. Immuno-haematologic aspects of dengue infection: biologic insights and clinical implications. Viruses, 16:1090, Jul 2024. URL: https://doi.org/10.3390/v16071090, doi:10.3390/v16071090. This article has 21 citations and is from a poor quality or predatory journal.

  7. (cherie2024immunohaematologicaspectsof pages 11-12): Tan Jiao Jie Cherie, Clarice Shi Hui Choong, Muhammad Bilal Abid, Matthew W. Weber, Eng Soo Yap, Suranjith L. Seneviratne, Visula Abeysuriya, and Sanjay de Mel. Immuno-haematologic aspects of dengue infection: biologic insights and clinical implications. Viruses, 16:1090, Jul 2024. URL: https://doi.org/10.3390/v16071090, doi:10.3390/v16071090. This article has 21 citations and is from a poor quality or predatory journal.

  8. (yuya2024progressandchallenges pages 12-12): Wang Yuya, Yang Yuansong, Liu Susu, Ling Chen, Wu Yong, Wang Yining, Wang YouChun, and Fan Changfa. Progress and challenges in development of animal models for dengue virus infection. Emerging Microbes & Infections, Sep 2024. URL: https://doi.org/10.1080/22221751.2024.2404159, doi:10.1080/22221751.2024.2404159. This article has 8 citations and is from a domain leading peer-reviewed journal.