| Literature DB >> 29746837 |
Matthew J Gorman1, Elizabeth A Caine2, Konstantin Zaitsev3, Matthew C Begley4, James Weger-Lucarelli5, Melissa B Uccellini6, Shashank Tripathi6, Juliet Morrison7, Boyd L Yount4, Kenneth H Dinnon4, Claudia Rückert5, Michael C Young5, Zhe Zhu8, Shelly J Robertson9, Kristin L McNally9, Jing Ye2, Bin Cao10, Indira U Mysorekar11, Gregory D Ebel5, Ralph S Baric4, Sonja M Best9, Maxim N Artyomov12, Adolfo Garcia-Sastre13, Michael S Diamond14.
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.Entities:
Keywords: RNA sequencing; Zika virus; flavivirus; immunity; infectious clone; interferon; pathogenesis; pregnancy; transgenic mice; vertical transmission
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Year: 2018 PMID： 29746837 PMCID： PMC5953559 DOI： 10.1016/j.chom.2018.04.003
Source DB: PubMed Journal: Cell Host Microbe ISSN： 1931-3128 Impact factor: 21.023