Editors' ChoiceViral Infection

A leak in the dike

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Sci. Signal.  15 Sep 2015:
Vol. 8, Issue 394, pp. ec266
DOI: 10.1126/scisignal.aad4153

Mosquitoes transmit dengue virus (DENV), which infects 100 million people each year and comes in several serotypes (1 to 4) and disease presentations–from mild infection to severe disease and sometimes death. Modhiran et al. and Beatty et al. implicate the circulating dengue virus nonstructural protein 1 (NS1) and the innate immune Toll-like receptor 4 (TLR4) in disease pathology and vaccine development. DENV infection protects a patient from future reinfection with the same DENV serotype, as well as producing temporary immune protection from severe dengue disease caused by a different DENV serotype. However, when the protected period passes, the patient becomes at increased risk for severe disease if infected with a second DENV serotype, which is believed to result from immunopathogenic processes that induce cytokine storm and cause vascular leakage that leads to shock. Beatty et al. showed that inoculation of mice with NS1 induces both vascular leak and secretion of inflammatory cytokines and that administration of NS1 with a sublethal dose of DENV2 leads to lethal vascular leak syndrome. In cultured human endothelial cell monolayers, NS1 from any of the four DENV serotypes triggered endothelial barrier permeability. NS1-immune polyclonal mouse serum or monoclonal antibodies to NS1 blocked the pathogenic effects of NS1 both in vivo and in vitro, and immunization of mice with NS1 protected against lethal DENV2 challenge. Modhiran et al. showed that highly purified NS1 acts as a pathogen-associated molecular pattern (PAMP) that stimulated mouse macrophages and human peripheral blood mononuclear cells (PBMCs) in culture through TLR4, resulting in release of inflammatory cytokines—an effect that was blocked by either a TLR4 antagonist or an anti-TLR4 antibody. Administration of a TLR4 antagonist quelled capillary leak in a mouse model of dengue virus infection, consistent with the endothelial barrier-disrupting activity of NS1 in vitro. Together, these findings highlight NS1 as an instigator of dengue-associated vascular leak and pinpoint a potential target for treating dengue symptoms and a component for developing dengue vaccines.

P. R. Beatty, H. Puerta-Guardo, S. S. Killingbeck, D. R. Glasner, K. Hopkins, E. Harris, Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination. Sci. Transl. Med. 7, 304ra141 (2015). [Abstract]

N. Modhiran, D. Watterson, D. A. Muller, A. K. Panetta, D. P. Sester, L. Liu, D. A. Hume, K. J. Stacey, P. R. Young, Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity. Sci. Transl. Med. 7, 304ra142 (2015). [Abstract]

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