Blockade of protease-activated receptor 2 (PAR-2) attenuates vascular dyshomeostasis and liver dysfunction induced by dengue virus infection

[Display omitted] The World Health Organization (WHO) recognizes dengue infection as a major public health concern in tropical and subtropical countries. Dengue infection is recognized as the second most deadly vector-borne disease in the world, based upon its incidence and mortality rate. Vascular dyshomeostasis and liver dysfunction are the major pathological manifestations in dengue patients. Vascular events in dengue patients include dropping of pulse rate, increased capillary leakage, hypotension, life-threatening hemorrhage due to release of inflammatory cytokines, growth factors, matrix metalloproteinase (MMP). The evident increase in cytokines, chemokines, and growth factors could further induce the release of pro- inflammatory cytokines and reactive oxygen species (ROS) by activating macrophages, monocytes, and T cells resulting in endothelial dysfunction and enhanced permeability in vessels. Moreover, the anti-dengue viral protein antibodies could target clotting cascades and endothelial cells, contributing to the vascular complications. Evidence has also indicated that infiltration of NK T cells and cytotoxic CD8+ cells during the early and late phases of dengue infection results in intra-hepatic damage. Several pieces of evidence have revealed that PAR-2 activation could regulate inflammatory cytokine release, immune cell activation, and endothelial cell damage. Thus, PAR-2 activation can be associated with vascular dyshomeostasis and hepatic dysfunction during critical phases of dengue infection. In this study, we correlate the pathological manifestations of dengue infection with PAR-2 activation and generate the proof-of-concept that targeting this receptor could abrogate these changes.