Gestational Stage and IFN-λ Signaling Regulate ZIKV Infection In Utero

Cell Host Microbe. 2017 Sep 13;22(3):366-376.e3. doi: 10.1016/j.chom.2017.08.012.

Abstract

Although Zika virus (ZIKV)-induced congenital disease occurs more frequently during early stages of pregnancy, its basis remains undefined. Using established type I interferon (IFN)-deficient mouse models of ZIKV transmission in utero, we found that the placenta and fetus were more susceptible to ZIKV infection at earlier gestational stages. Whereas ZIKV infection at embryonic day 6 (E6) resulted in placental insufficiency and fetal demise, infections at midstage (E9) resulted in reduced cranial dimensions, and infection later in pregnancy (E12) caused no apparent fetal disease. In addition, we found that fetuses lacking type III IFN-λ signaling had increased ZIKV replication in the placenta and fetus when infected at E12, and reciprocally, treatment of pregnant mice with IFN-λ2 reduced ZIKV infection. IFN-λ treatment analogously diminished ZIKV infection in human midgestation fetal- and maternal-derived tissue explants. Our data establish a model of gestational stage dependence of ZIKV pathogenesis and IFN-λ-mediated immunity at the maternal-fetal interface.

Keywords: Zika virus; flavivirus; gestational stage; host immunity; innate immunity; interferon lambda; pathogenesis; pregnancy.

MeSH terms

  • Animals
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Female
  • Fetal Diseases / genetics
  • Fetal Diseases / metabolism
  • Fetal Diseases / physiopathology
  • Fetal Diseases / virology*
  • Gestational Age
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pregnancy
  • Pregnancy Complications, Infectious / genetics
  • Pregnancy Complications, Infectious / metabolism
  • Pregnancy Complications, Infectious / physiopathology
  • Pregnancy Complications, Infectious / virology*
  • Receptors, Interferon / genetics
  • Receptors, Interferon / metabolism
  • Zika Virus / genetics
  • Zika Virus / physiology*
  • Zika Virus Infection / embryology*
  • Zika Virus Infection / metabolism*
  • Zika Virus Infection / physiopathology
  • Zika Virus Infection / virology

Substances

  • Cytokines
  • IFNLR1 protein, mouse
  • Receptors, Interferon
  • interferon-lambda protein, mouse