Dengue Virus NS1 Disrupts the Endothelial Glycocalyx, Leading to Hyperpermeability

Henry Puerta-Guardo, Dustin R. Glasner, Eva Harris

PLoS Pathog. 2016 Jul 14;12(7):e1005738

Speaker：Yu-Ling Chen (陳又菱)                               Time：13:10~14:00, Nov. 2, 2016

Commentator：Dr. Yee-Shin Lin (林以行 教授)        Place：Room 601

Abstract:

Dengue virus (DENV) is a single positive RNA virus. DENV genome encodes for 3 structural (C, prM and E) and 7 nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5). NS1, the nonstructural protein of dengue virus, which is playing distinct functions in immune response, pathogenesis and viral replication. Dengue is a mosquito-borne human disease. Infection with dengue virus causes diseases ranging from mild dengue fever to severe dengue. Moreover, increased vascular permeability is primary manifestation of severe dengue. As we know, DENV NS1 alone can trigger endothelial hyperpermeability, resulting in vascular leakage¹. DENV NS1 protein activates cells via Toll-like receptor 4 (TLR4) and disrupts endothelial cell monolayer integrity²_.Endothelial glycocalyx layer (EGL), a layer of membrane-bound proteoglycans and glycoprotein, composed of glycocalyx found on endothelial cells. Hence, the author finds that DENV NS1 induces sialic acid (Sia) degradation and shedding of heparin sulfate proteoglycans (HSPGs) in the EGL of endothelial cells. When endothelial cells are under NS1 treatment, cathepsin L, involved in the initiation of protein degradation, is activated to take apart in heparanase. Activated heparanase can specifically inhibit sialidase, which cleavages Sia. The effect can prohibit DENV NS1-induced EGL disruption and endothelial hyperpermeability. Subsequently, the author finds that TLR4 may be involved in Sia disruption in the EGL of human pulmonary microvascular endothelial cells (HPMEC) but has a little affection on cathepsin L-heparanase pathway following binding of DENV NS1. In conclusion, the author points out that NS1 from all four DENV serotypes induce hyperpermeability in endothelial cells through cathepsin-L heparanase pathway.

References：

1. Beatty PR.et al. (2015)Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination. Sci Transl Med. 7(304):304ra141.

2. Modhiran N.et al. (2015)Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity. Sci Transl Med. 7(304):304ra142.