An Immunocompetent Mouse Model of Zika Virus Infection

Cell Host Microbe. 2018 May 9;23(5):672-685.e6. doi: 10.1016/j.chom.2018.04.003.

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.

Keywords: RNA sequencing; Zika virus; flavivirus; immunity; infectious clone; interferon; pathogenesis; pregnancy; transgenic mice; vertical transmission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain
  • Cell Survival
  • Disease Models, Animal
  • Female
  • Fetal Diseases / metabolism
  • Fetal Diseases / virology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Immunity
  • Infectious Disease Transmission, Vertical
  • Interferon-beta / metabolism
  • Interferons / metabolism
  • Mice / genetics
  • Mice / immunology*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Placenta / metabolism
  • Pregnancy
  • Pregnancy Complications, Infectious / virology
  • RNA Helicases / genetics
  • Receptor, Interferon alpha-beta
  • STAT2 Transcription Factor / metabolism
  • Serine Endopeptidases / genetics
  • Viral Nonstructural Proteins / genetics
  • Zika Virus / genetics
  • Zika Virus / immunology*
  • Zika Virus / pathogenicity*
  • Zika Virus Infection / immunology*
  • Zika Virus Infection / virology

Substances

  • Homeodomain Proteins
  • Ifnar1 protein, mouse
  • NS3 protein, flavivirus
  • NS4B protein, flavivirus
  • STAT2 Transcription Factor
  • Viral Nonstructural Proteins
  • RAG-1 protein
  • Receptor, Interferon alpha-beta
  • Interferon-beta
  • Interferons
  • Serine Endopeptidases
  • RNA Helicases