@article{fdi:010076235,
  title = {{A} {T}164{S} mutation in the dengue virus {NS}1 protein is associated with greater disease severity in mice},
  author = {{C}han, {K}. {W}. {K}. and {W}atanabe, {S}. and {J}in, {J}. {Y}. and {P}ompon, {J}ulien and {T}eng, {D}. and {A}lonso, {S}. and {V}ijaykrishna, {D}. and {H}alstead, {S}. {B}. and {M}arzinek, {J}. {K}. and {B}ond, {P}. {J}. and {B}urla, {B}. and {T}orta, {F}. and {W}enk, {M}. {R}. and {O}oi, {E}. {E}. and {V}asudevan, {S}. {G}.},
  editor = {},
  language = {{ENG}},
  abstract = {{D}engue viruses cause severe and sudden human epidemics worldwide. {T}he secreted form of the nonstructural protein 1 (s{NS}1) of dengue virus causes vascular leakage, a hallmark of severe dengue disease. {H}ere, we reverse engineered the {T}164{S} mutation of {NS}1, associated with the severity of dengue epidemics in the {A}mericas, into a dengue virus serotype 2 mildly infectious strain. {T}he {T}164{S} mutant virus decreased infectious virus production and increased s{NS}1 production in mammalian cell lines and human peripheral blood mononuclear cells ({PBMC}s) without affecting viral {RNA} replication. {G}ene expression profiling of 268 inflammation-associated human genes revealed up-regulation of genes induced in response to vascular leakage. {I}nfection of the mosquito vector {A}edes aegypti with the {T}164{S} mutant virus resulted in increased viral load in the mosquito midgut and higher s{NS}1 production compared to wild-type virus infection. {I}nfection of type 1 and 2 interferon receptor-deficient {AG}129 mice with the {T}164{S} mutant virus resulted in severe disease coupled with increased complement activation, tissue inflammation, and more rapid mortality compared to {AG}129 mice infected with wild-type virus. {M}olecular dynamics simulations predicted that mutant s{NS}1 formed stable dimers similar to the wild-type protein, whereas the hexameric mutant s{NS}1 was predicted to be unstable. {I}mmunoaffinity-purified s{NS}1 from {T}164{S} mutant virus-infected mammalian cells was associated with different lipid classes compared to wild-type s{NS}1. {T}reatment of human {PBMC}s with s{NS}1 purified from {T}164{S} mutant virus resulted in a twofold higher production of proinflammatory cytokines, suggesting a mechanism for how mutant s{NS}1 may cause more severe dengue disease.},
  keywords = {},
  booktitle = {},
  journal = {{S}cience {T}ranslational {M}edicine},
  volume = {11},
  numero = {498},
  pages = {eaat7726 [15 p.]},
  ISSN = {1946-6234},
  year = {2019},
  DOI = {10.1126/scitranslmed.aat7726},
  URL = {https://www.documentation.ird.fr/hor/fdi:010076235},
}