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IFITM proteins inhibit placental syncytiotrophoblast formation and promote fetal demise

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Science  12 Jul 2019:
Vol. 365, Issue 6449, pp. 176-180
DOI: 10.1126/science.aaw7733

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Placenta formation and fetal demise

A critical step of placental development is the fusion of trophoblast cells into a multi-nucleated syncytiotrophoblast layer. Trophoblast fusion is mediated by syncytins, encoded by endogenous retrovirus–derived envelope glycoproteins. Buchrieser et al. report that interferon-induced transmembrane (IFITM) proteins inhibit syncytin-mediated syncytiotrophoblast formation, restricting placental development and triggering fetal demise (see the Perspective by Kellam and Weiss). The results provide a molecular explanation for the placental dysfunctions observed in interferon-mediated disorders such as intrauterine growth retardation, TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpes) infections, and some forms of preeclampsia.

Science, this issue p. 176; see also p. 118

Abstract

Elevated levels of type I interferon (IFN) during pregnancy are associated with intrauterine growth retardation, preterm birth, and fetal demise through mechanisms that are not well understood. A critical step of placental development is the fusion of trophoblast cells into a multinucleated syncytiotrophoblast (ST) layer. Fusion is mediated by syncytins, proteins deriving from ancestral endogenous retroviral envelopes. Using cultures of human trophoblasts or mouse cells, we show that IFN-induced transmembrane proteins (IFITMs), a family of restriction factors blocking the entry step of many viruses, impair ST formation and inhibit syncytin-mediated fusion. Moreover, the IFN inducer polyinosinic:polycytidylic acid promotes fetal resorption and placental abnormalities in wild-type but not in Ifitm-deleted mice. Thus, excessive levels of IFITMs may mediate the pregnancy complications observed during congenital infections and other IFN-induced pathologies.

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