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

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

Jagger BW¹, Miner JJ², Cao B³, Arora N⁴, Smith AM¹, Kovacs A⁵, Mysorekar IU⁶, Coyne CB⁴, Diamond MS⁷.

Author information

1: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
2: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
3: Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA.
4: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA; Center for Microbial Pathogenesis, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA.
5: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
6: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA.
7: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: diamond@wusm.wustl.edu.

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.