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.
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
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
name: Dengue
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-02-16T20:19:38Z'
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.
phenotypes:
- name: Fever
category: Systemic
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Fever
term:
id: HP:0001945
label: Fever
evidence:
- reference: PMID:17448935
reference_title: "Chikungunya, an epidemic arbovirosis."
supports: NO_EVIDENCE
snippet: The disease typically consists of an acute illness characterised by fever, rash, and incapacitating arthralgia.
explanation: Fever is a typical clinical feature of dengue.
- name: Skin rash
category: Dermatologic
frequency: FREQUENT
phenotype_term:
preferred_term: Skin rash
term:
id: HP:0000988
label: Skin rash
evidence:
- reference: PMID:17448935
reference_title: "Chikungunya, an epidemic arbovirosis."
supports: NO_EVIDENCE
snippet: The disease typically consists of an acute illness characterised by fever, rash, and incapacitating arthralgia.
explanation: Rash is a typical clinical feature of dengue.