Role of dengue secreted nonstructural protein 1 in severe dengue disease

November 14, 2019

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The secreted form of the nonstructural protein 1 (sNS1) of dengue virus causes vascular leakage, which is seen in severe dengue disease. The authors reverse engineered the T164S mutation of NS1, previously found to be associated with the severity of dengue epidemics in the Americas, into a dengue virus serotype 2 mildly infectious strain. They found that the resultant T164S mutant virus decreased infectious virus production and increased sNS1 production in mammalian cell lines and human peripheral blood mononuclear cells (PBMCs), without affecting viral RNA replication. Gene expression profiling of 268 inflammation-associated human genes revealed upregulation of the genes induced in response to vascular leakage. When Aedes aegypti was infected with this T164S mutant virus, there was an increase in viral load in the mosquito midgut, together with higher sNS1 production compared with wild-type virus infection. Infection of type 1 and 2 interferon receptor-deficient AG129 mice with the T164S mutant virus resulted in severe disease together with increased complement activation, tissue inflammation and more rapid mortality. The authors found that molecular dynamics simulations could predict that mutant sNS1 forms stable dimers similar to the wild-type protein, while the hexameric mutant sNS1 was predicted to be unstable. Immunoaffinity-purified sNS1 from T164S mutant virus-infected mammalian cells was associated with different lipid classes compared with wild-type sNS1, and treatment of human PBMCs with T164S-sNS1 led to a twofold higher production of proinflammatory cytokines. This outlines a potential mechanism for how mutant sNS1 may cause more severe dengue disease.

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Chan KWK, Watanabe S, Jin JY, Pompon J, Teng D, et al. ISSN: Sci Transl Med; 11(498): pii: eaat7726


Added: November 14, 2019