Suppression of human trophoblast syncytialization by human cytomegalovirus infection

Nobuko Mimura; Takeshi Nagamatsu; Kazuki Morita; Ayumi Taguchi; Takashi Toya; Keiichi Kumasawa; Takayuki Iriyama; Kei Kawana; Naoki Inoue; Tomoyuki Fujii; Yutaka Osuga

doi:10.1016/j.placenta.2021.12.011

Suppression of human trophoblast syncytialization by human cytomegalovirus infection

Placenta. 2022 Jan:117:200-208. doi: 10.1016/j.placenta.2021.12.011. Epub 2021 Dec 11.

Authors

Affiliations

¹ Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
² Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan. Electronic address: tnag-tky@umin.ac.jp.
³ Hematology Division, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.
⁴ Department of Obstetrics and Gynecology, Faculty of Medicine, Nihon University, Japan.
⁵ Microbiology and Immunology, Gifu Pharmaceutical University, Gifu, Japan.

PMID: 34933151
DOI: 10.1016/j.placenta.2021.12.011

Abstract

Introduction: Placental dysfunction triggers fetal growth restriction in congenital human cytomegalovirus (HCMV) infection. Studies suggest that HCMV infection interferes with the differentiation of human trophoblasts. However, the underlying mechanisms have not been clarified. This study investigated the impact of HCMV infection on gene transcriptomes in cytotrophoblasts (CTBs) associated with placental dysfunction.

Methods: CTBs were isolated from human term placentas, and spontaneous syncytialization was observed in vitro. The transcriptome profiles were compared between CTB groups with and without HCMV infection by cap analysis gene expression sequencing. The effect of HCMV infection on trophoblast differentiation was evaluated by examining cell fusion status using immunocytochemical staining for desmoplakin and assessing the production of cell differentiation markers, including hCG, PlGF, and soluble Flt-1, using ELISA.

Results: The expression of the genes categorized in the signaling pathways related to the cell cycle was significantly enhanced in CTBs with HCMV infection compared with uninfected CTBs. HCMV infection hindered the alteration of the gene expression profile associated with syncytialization. This suppressive effect under HCMV infection was concurrent with the reduction in hCG and PlGF secretion. Immunostaining for desmoplakin revealed that HCMV infection reduced the cell fusion of cultured CTBs. These findings imply that HCMV infection has a negative impact on syncytialization, which is indispensable for the maintenance of villous function.

Discussion: HCMV infection interferes with gene expression profiles and functional differentiation of trophoblasts. Suppression of syncytialization may be a survival strategy for HCMV to expand infection and could be associated with placental dysfunction.

Keywords: Cytomegalovirus; Cytotrophoblast; Placenta; Placental growth factor; Syncytialization; Syncytiotrophoblast.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation*
Cytomegalovirus Infections / metabolism
Cytomegalovirus Infections / physiopathology*
Female
Humans
Pregnancy
Primary Cell Culture
Transcriptome*
Trophoblasts / physiology*