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Sci Immunol. 2018 Jan 5;3(19). pii: eaao1680. doi: 10.1126/sciimmunol.aao1680.

Type I interferons instigate fetal demise after Zika virus infection.

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
3
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
4
Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
5
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
6
Yale School of Public Health, New Haven, CT 06520, USA.
7
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine New Haven, CT 06520, USA.
8
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
9
Center for Microbial Pathogenesis, Children's Hospital of Pittsburgh of UPMC (University of Pittsburgh Medical Center), Pittsburgh, PA 15224, USA.
10
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. akiko.iwasaki@yale.edu.

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.

PMID:
29305462
PMCID:
PMC6049088
[Available on 2019-01-05]
DOI:
10.1126/sciimmunol.aao1680

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