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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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
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.
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: Plasma leakage leading to shock in severe dengue
description: Severe dengue involves plasma leakage that can progress to hypovolemic shock.
evidence:
- reference: PMID:32265181
reference_title: "Dengue hemorrhagic fever - A systemic literature review of current perspectives on pathogenesis, prevention and control."
supports: SUPPORT
snippet: Plasma leakages is the main pathophysiological hallmark that distinguishes DHF from DF. Severe plasma leakage can result in hypovolemic shock.
explanation: The review highlights plasma leakage and shock in severe dengue.
- 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 leading to shock in severe dengue
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.
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.
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.
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.
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).
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):
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
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