Research ArticleANTIVIRAL IMMUNITY

Type I interferons instigate fetal demise after Zika virus infection

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Science Immunology  05 Jan 2018:
Vol. 3, Issue 19, eaao1680
DOI: 10.1126/sciimmunol.aao1680

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The interferon boomerang

Interferon-α/β receptor (IFNAR)–deficient mice are highly susceptible to viruses, including Zika virus (ZIKV). Previous studies modeled ZIKV infection during pregnancy in mice by crossing Ifnar1−/− females to wild-type males, generating Ifnar1+/− fetuses that retain type I interferon (IFN) responsiveness. Yockey et al. have directly examined the role of fetal type I IFN signaling in protection in this context, by crossing Ifnar1−/− females to Ifnar1+/− males. Although Ifnar1−/− fetuses had higher ZIKV titers as compared with Ifnar1+/− fetuses, Ifnar1−/− fetuses survived longer. Furthermore, they found that activation of type I IFN signaling in the placentas of Ifnar1+/− fetuses led to fetal hypoxia, demise, and resorption. Beyond ZIKV infection, the study calls for closer examination of the role of IFNs in pregnancy-associated complications.

Abstract

Zika virus (ZIKV) infection during pregnancy is associated with adverse fetal outcomes, including microcephaly, growth restriction, and fetal demise. Type I interferons (IFNs) are essential for host resistance against ZIKV, and IFN-α/β receptor (IFNAR)–deficient mice are highly susceptible to ZIKV infection. Severe fetal growth restriction with placental damage and fetal resorption is observed after ZIKV infection of type I IFN receptor knockout (Ifnar1−/−) dams mated with wild-type sires, resulting in fetuses with functional type I IFN signaling. The role of type I IFNs in limiting or mediating ZIKV disease within this congenital infection model remains unknown. In this study, we challenged Ifnar1−/− dams mated with Ifnar1+/− sires with ZIKV. This breeding scheme enabled us to examine pregnant dams that carry a mixture of fetuses that express (Ifnar1+/−) or do not express IFNAR (Ifnar1−/−) within the same uterus. Virus replicated to a higher titer in the placenta of Ifnar1−/− than within the Ifnar1+/− concepti. Yet, rather unexpectedly, we found that only Ifnar1+/− fetuses were resorbed after ZIKV infection during early pregnancy, whereas their Ifnar1−/− littermates continue to develop. Analyses of the fetus and placenta revealed that, after ZIKV infection, IFNAR signaling in the conceptus inhibits development of the placental labyrinth, resulting in abnormal architecture of the maternal-fetal barrier. Exposure of midgestation human chorionic villous explants to type I IFN, but not type III IFNs, altered placental morphology and induced cytoskeletal rearrangements within the villous core. Our results implicate type I IFNs as a possible mediator of pregnancy complications, including spontaneous abortions and growth restriction, in the context of congenital viral infections.

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