IFITM proteins inhibit placental syncytiotrophoblast formation and promote fetal demise

• Published in: Science (American Association for the Advancement of Science) Vol. 365; no. 6449; pp. 176 - 180
• Main Authors: Buchrieser, Julian, Degrelle, Séverine A, Couderc, Thérèse, Nevers, Quentin, Disson, Olivier, Manet, Caroline, Donahue, Daniel A, Porrot, Françoise, Hillion, Kenzo-Hugo, Perthame, Emeline, Arroyo, Marlene V, Souquere, Sylvie, Ruigrok, Katinka, Dupressoir, Anne, Heidmann, Thierry, Montagutelli, Xavier, Fournier, Thierry, Lecuit, Marc, Schwartz, Olivier
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 12.07.2019; American Association for the Advancement of Science (AAAS)
• Subjects: Abnormalities; Animals; Antigens, Differentiation - immunology; Apoptosis Regulatory Proteins - immunology; Cell Fusion; Complications; Cytomegalovirus; Endogenous retroviruses; Female; Fetal Death - etiology; Fetal resorption; Fetal Resorption - immunology; Fetuses; Gene Products, env - immunology; Glycoproteins; Growth rate; Human health and pathology; Humans; Immunology; Infections; Intellectual Disability; Interferon; Interferon Type I - immunology; Intracellular Signaling Peptides and Proteins - immunology; Life Sciences; Membrane proteins; Mice; Microbiology and Parasitology; Placenta; Poly I-C - pharmacology; Pre-eclampsia; Pregnancy; Pregnancy complications; Pregnancy Proteins - immunology; Premature birth; Prenatal development; Proteins; RNA-Binding Proteins - immunology; Syncytin; Toxoplasmosis; Trophoblasts; Trophoblasts - drug effects; Trophoblasts - immunology; Virology; Viruses
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aaw7733

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 deleted mice. Thus, excessive levels of IFITMs may mediate the pregnancy complications observed during congenital infections and other IFN-induced pathologies.