The contribution of placental immune responses to congenital Zika virus (ZIKV) syndrome remains poorly understood. Here, we leveraged a mouse model of ZIKV infection to identify mechanisms of innate immune restriction exclusively in the fetal compartment of the placenta. ZIKV principally infected mononuclear trophoblasts in the junctional zone, which was limited by mitochondrial antiviral-signaling protein (MAVS) and type I interferon (IFN) signaling mechanisms. Single nuclear RNA sequencing revealed MAVS-dependent expression of IFN-stimulated genes (ISGs) in spongiotrophoblasts but not in other placental cells that use alternate pathways to induce ISGs. ZIKV infection of Ifnar1−/− or Mavs−/− placentas was associated with greater infection of the adjacent immunocompetent decidua, and heterozygous Mavs+/− or Ifnar1+/− dams carrying immunodeficient fetuses sustained greater maternal viremia and tissue infection than dams carrying wild-type fetuses. Thus, MAVS-IFN signaling in the fetus restricts ZIKV infection in junctional zone trophoblasts, which modulates dissemination and outcome for both the fetus and the pregnant mother.
Fetal MAVS and type I IFN signaling pathways control ZIKV infection in the placenta and maternal decidua
Disclosures: M.S. Diamond reported personal fees from Inbios, Ocugen, Akagera Medicines, Merck, and GlaxoSmithKline, grants from Emergent Biosolutions, and personal fees and grants from Vir Biotechnology, IntegerBio, and Moderna outside the submitted work. No other disclosures were reported.
M. Elam-Noll died on February 25, 2023.
- Award Id(s): R01 AI14582804,R01 AI1459604,P30 AR074992,S10 RR027552,P30 AR073752,DK131107
- Award Id(s): P30 CA91842
- Award Id(s): INV-033564
Yael Alippe, Leran Wang, Reyan Coskun, Stéfanie P. Muraro, Fang R. Zhao, Michelle Elam-Noll, J. Michael White, Daiana M. Vota, Vanesa C. Hauk, Jeffrey I. Gordon, Scott A. Handley, Michael S. Diamond; Fetal MAVS and type I IFN signaling pathways control ZIKV infection in the placenta and maternal decidua. J Exp Med 2 September 2024; 221 (9): e20240694. doi: https://doi.org/10.1084/jem.20240694
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