Human cytomegalovirus infection interferes with the maintenance and differentiation of trophoblast progenitor cells of the human placenta

Takako Tabata, Matthew Petitt, Martin Zydek, June Fang-Hoover, Nicholas Larocque, Mitsuru Tsuge, Matthew Gormley, Lawrence M. Kauvar, Lenore Pereira

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24 Citations (Scopus)

Abstract

Human cytomegalovirus (HCMV) is a major cause of birth defects that include severe neurological deficits, hearing and vision loss, and intrauterine growth restriction. Viral infection of the placenta leads to development of avascular villi, edema, and hypoxia associated with symptomatic congenital infection. Studies of primary cytotrophoblasts (CTBs) revealed thatHCMVinfection impedes terminal stages of differentiation and invasion by various molecular mechanisms. Werecently discovered thatHCMVarrests earlier stages involving development of human trophoblast progenitor cells (TBPCs), which give rise to the mature cell types of chorionic villi- syncytiotrophoblasts on the surfaces of floating villi and invasive CTBs that remodel the uterine vasculature. Here, we show that viral proteins are present in TBPCs of the chorion in cases of symptomatic congenital infection. In vitro studies revealed thatHCMV replicates in continuously self-renewing TBPC lines derived from the chorion and alters expression and subcellular localization of proteins required for cell cycle progression, pluripotency, and early differentiation. In addition, treatment with a human monoclonal antibody toHCMVglycoprotein B rescues differentiation capacity, and thus, TBPCs have potential utility for evaluation of the efficacies of novel antiviral antibodies in protecting and restoring placental development. Our results suggest thatHCMVreplicates in TBPCs in the chorion in vivo, interfering with the earliest steps in the growth of new villi, contributing to virus transmission and impairing compensatory development. In cases of congenital infection, reduced responsiveness of the placenta to hypoxia limits the transport of substances from maternal blood and contributes to fetal growth restriction.

Original languageEnglish
Pages (from-to)5134-5147
Number of pages14
JournalJournal of Virology
Volume89
Issue number9
DOIs
Publication statusPublished - 2015

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Tabata, T., Petitt, M., Zydek, M., Fang-Hoover, J., Larocque, N., Tsuge, M., Gormley, M., Kauvar, L. M., & Pereira, L. (2015). Human cytomegalovirus infection interferes with the maintenance and differentiation of trophoblast progenitor cells of the human placenta. Journal of Virology, 89(9), 5134-5147. https://doi.org/10.1128/JVI.03674-14