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An Immunocompetent Mouse Model of Zika Virus Infection.

  • Author(s): Gorman, Matthew J
  • Caine, Elizabeth A
  • Zaitsev, Konstantin
  • Begley, Matthew C
  • Weger-Lucarelli, James
  • Uccellini, Melissa B
  • Tripathi, Shashank
  • Morrison, Juliet
  • Yount, Boyd L
  • Dinnon, Kenneth H
  • Rückert, Claudia
  • Young, Michael C
  • Zhu, Zhe
  • Robertson, Shelly J
  • McNally, Kristin L
  • Ye, Jing
  • Cao, Bin
  • Mysorekar, Indira U
  • Ebel, Gregory D
  • Baric, Ralph S
  • Best, Sonja M
  • Artyomov, Maxim N
  • Garcia-Sastre, Adolfo
  • Diamond, Michael S
  • et al.
Abstract

Progress toward understanding Zika virus (ZIKV) pathogenesis is hindered by lack of immunocompetent small animal models, in part because ZIKV fails to effectively antagonize Stat2-dependent interferon (IFN) responses in mice. To address this limitation, we first passaged an African ZIKV strain (ZIKV-Dak-41525) through Rag1-/- mice to obtain a mouse-adapted virus (ZIKV-Dak-MA) that was more virulent than ZIKV-Dak-41525 in mice treated with an anti-Ifnar1 antibody. A G18R substitution in NS4B was the genetic basis for the increased replication, and resulted in decreased IFN-β production, diminished IFN-stimulated gene expression, and the greater brain infection observed with ZIKV-Dak-MA. To generate a fully immunocompetent mouse model of ZIKV infection, human STAT2 was introduced into the mouse Stat2 locus (hSTAT2 KI). Subcutaneous inoculation of pregnant hSTAT2 KI mice with ZIKV-Dak-MA resulted in spread to the placenta and fetal brain. An immunocompetent mouse model of ZIKV infection may prove valuable for evaluating countermeasures to limit disease.

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