Dengue virus non-structural protein 1: a pathogenic factor, therapeutic target, and vaccine candidate

Abstract

Dengue virus (DENV) infection is the most common mosquito-transmitted viral infection. DENV infection can cause mild dengue fever or severe dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS). Hemorrhage and vascular leakage are two characteristic symptoms of DHF/DSS. However, due to the limited understanding of dengue pathogenesis, no satisfactory therapies to treat nor vaccine to prevent dengue infection are available, and the mortality of DHF/DSS is still high. DENV nonstructural protein 1 (NS1), which can be secreted in patients' sera, has been used as an early diagnostic marker for dengue infection for many years. However, the roles of NS1 in dengue-induced vascular leakage were described only recently. In this article, the pathogenic roles of DENV NS1 in hemorrhage and vascular leakage are reviewed, and the possibility of using NS1 as a therapeutic target and vaccine candidate is discussed.

Keywords: Coagulopathy; Dengue virus (DENV); Hemorrhage; Nonstructural protein 1 (NS1); Vaccine; Vascular leakage.

Fig. 1

The possible mechanisms by which DENV NS1 causes vascular leakage. (1a) NS1 binding to TLR4 of PBMCs induces the expression and secretion of TNF-α, IL-1β and IL-6 cytokines, which may disrupt the tight junction, leading to vascular leakage [40]. (1b) NS1 binding to TLR4 or (2a) other molecules on endothelial cells induces the secretion of MIF [43]. (2b) MIF binding to its receptor on endothelial cells induces junction disruption through autophagic degradation of junction proteins such as ZO-1 and VE-cadherin [43]. (3) Binding of NS1 to endothelial cells also induces HPA-1 activation through cathepsin L, leading to endothelial glycocalyx degradation and vascular leakage [42, 49]. (4a) Additionally, NS1-induced MIF secretion is also involved in HPA-1 secretion of endothelial cells, and (4b) MMP-9 secretion of WBCs which can also contribute to endothelial glycocalyx degradation [65]

Fig. 2

The possible pathogenic roles of DENV NS1 and its potential as a therapeutic target against DENV infection