Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity

Naphak Modhiran, Daniel Watterson, David A. Muller, Adele K. Panetta, David P. Sester, Lidong Liu, David A. Hume, Katryn J. Stacey, Paul R. Young

Sci Transl Med. 2015 Sep 9;7(304)

Speaker: Chia-Yi Hung (洪嘉依)                                  Time: 13:10~14:00, March 9, 2016

Commentator: Dr. Trai-Ming Yeh (葉才明 老師)          Place: Room 601

Abstract:

Dengue virus (DENV) infection is an important problem in tropical and subtropical areas. Infection with any of the four DENV serotypes results in a range of syndromes from inapparent infection,  classic dengue fever to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) which is characterized by vascular leakage and shock. In comparison with less severe cases, DHF/DSS patients have higher levels of circulating proinflammatory cytokines and chemokines, referred to as a cytokine storm which is thought to play a major role in the collapse of vascular integrity. Both activated T cells and monocytes have been proposed to play critical roles in cytokines and chemokines production (1). The DENV nonstructure protein NS1 is a multifunctional glycoprotein and can be secreted as a soluble, lipid-associated hexameric species. High levels of secreted NS1 (sNS1) are associated with increased disease severity, although it is unclear whether this measure has functional significance (2). In this study, the authors examined whether sNS1 directly stimulates innate immune responses. They found that purified sNS1 which was shown to be LPS-free and LPS both strongly induced the secretion of interleukin-6 (IL-6) from peripheral blood mononuclear cells (PBMCs), suggesting that NS1 behaves as a pathogen-associated molecular patterns (PAMPs). Besides, NS1 induced a dose-dependent increase in the levels of mRNA for TNF-a and IL-6 in mouse bone marrow-derived macrophages (BMMs). Furthermore, they discovered NS1 was recognized via TLR4 and induced proinflammatory cytokines in mouse BMM and human PBMCs. In the end, they analyzed the effect of exposure to NS1 or LPS on the integrity of human microvasculature endothelial cell monolayers and the results implied that in addition to mediating cytokine induction from monocytes or macrophages, NS1 recognition by TLR4 on endothelial cells directly contributes to vascular leak. Furthermore, a TLR4 antagonist protects against vascular leak in a mouse model of DENV infection. Taken together, inhibition of NS1-mediated TLR4 activation may offer a new DENV intervention strategy.

References:

1. A. L. Rothman. (2011) Immunity to dengue virus: A tale of original antigenic sin and tropical cytokine storms. Nat. Rev. Immunol. 11: 532–543.
2. P. Avirutnan. et al. (2006) Vascular leakage in severe dengue virus infections: A potential role for the nonstructural viral protein NS1 and complement. J. Infect. Dis. 193: 1078–1088.