An Immunocompetent Mouse Model of Zika Virus Infection

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

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

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. An immunocompetent mouse model of ZIKV infection is needed. Gorman et al. generated ZIKV-Dak-MA, a strain with a mutation in NS4B that causes greater disease in mice than the parental virus. Human STAT2 knockin mice were generated and challenged with ZIKV-Dak-MA to establish a fully immunocompetent ZIKV mouse model.

Original languageEnglish
Pages (from-to)672-685.e6
JournalCell Host and Microbe
Volume23
Issue number5
DOIs
StatePublished - May 9 2018

Keywords

  • RNA sequencing
  • Zika virus
  • flavivirus
  • immunity
  • infectious clone
  • interferon
  • pathogenesis
  • pregnancy
  • transgenic mice
  • vertical transmission

Fingerprint Dive into the research topics of 'An Immunocompetent Mouse Model of Zika Virus Infection'. Together they form a unique fingerprint.

Cite this