Details

Autor(en) / Beteiligte

• 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.

Titel

An Immunocompetent Mouse Model of Zika Virus Infection

Ist Teil von

• Cell host & microbe, 2018-05, Vol.23 (5), p.672-685.e6

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •A mouse-adapted ZIKV (Dak-MA) with enhanced brain and NSC infectivity was generated•NS4B G18R mutation enhances pathogenicity of African and American ZIKV strains•Immunocompetent human STAT2 knockin mice generated that are susceptible to ZIKV NS4B G18R•ZIKV-Dak-MA spreads to the placenta and fetus in immunocompetent hSTAT2 knockin mice 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.