Insights into potential causes of vascular hyperpermeability in dengue

Dengue is a mosquito-borne disease caused by dengue virus (DENV), where four serotypes can infect humans. Most DENV infections are self-resolving, but in some individuals, severe dengue characterised by a sudden increase in haematocrit, rapid decrease in platelet counts, and vascular leakage is a complication [1,2]. In severe dengue, a major pathogenic mechanism is a transient increase in vascular permeability resulting in severe plasma leakage (herein referred to vascular hyperpermeability) leading to hypotension, circulatory collapse, and organ dysfunction [1]. The precise mechanism in DENV-associated vascular hyperpermeability is unclear, and several hypotheses including antibody-dependent enhancement (ADE) and “cytokine storm” have been proposed. In ADE, suboptimal DENV neutralising antibodies against a heterologous serotype (in secondary infection) promotes DENV uptake into immunological cells, increasing infection and viral replication that can exacerbate the immune response [3]. Similarly, infected monocytes release excessive amounts of proinflammatory cytokines and, if dysregulated, can lead to “cytokine storm” [4]. In this article, we present current understandings on the potential causes of dengue-associated vascular hyperpermeability, which is a consequence of complex interactions between the virus and the host endothelium immune response. ; Nanyang Technological University ; National Medical Research Council (NMRC) ; Published version ; AT is supported by Nanyang Technological University Research Scholarship Block Fellowship of Singapore and Lee Kong Chian School of Medicine, Singapore, Start-up grant. CLLC receives support from Ministry of Education (MOE) Fundamental Research Grant Scheme of Malaysia: ID FRGS/1/2020/SKK0/TAYLOR/02/1. PYC is supported by NMRC Research Training Fellowship (NMRC/Fellowship/0056/2018). TWY is supported by Lee Kong Chian School of Medicine Singapore, Start-up grant.