The Placental Response to Guinea Pig Cytomegalovirus Depends Upon the Timing of Maternal Infection

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Abstract

Human cytomegalovirus (HCMV) infects the placenta, and these placental infections can cause fetal injury and/or demise. The timing of maternal HCMV infection during pregnancy is a determinant of fetal outcomes, but how development affects the placenta’s susceptibility to infection, the likelihood of placental injury post-infection, and the frequency of transplacental HCMV transmission remains unclear. In this study, guinea pig cytomegalovirus (GPCMV) was used to model primary maternal infection and compare the effects of infection at two different times on the placenta. When guinea pigs were infected with GPCMV at either 21- or 35-days gestation (dGA), maternal and placental viral loads, as determined by droplet digital PCR, were not significantly affected by the timing of maternal infection. However, when the transcriptomes of gestational age-matched GPCMV-infected and control placentas were compared, significant infection-associated changes in gene expression were only observed after maternal infection at 35 dGA. Notably, transcripts associated with immune activation (e.g. Cxcl10, Ido1, Tgtp1, and Tlr8) were upregulated in the infected placenta. A GPCMV-specific in situ hybridization assay detected rare infected cells in the main placenta after maternal infection at either time, and maternal infection at 35 dGA also caused large areas of GPCMV-infected cells in the junctional zone. As GPCMV infection after mid-gestation is known to cause high rates of stillbirth and/or fetal growth restriction, our results suggest that the placenta becomes sensitized to infection-associated injury late in gestation, conferring an increased risk of adverse pregnancy outcomes after cytomegalovirus infection.

Original languageEnglish (US)
Article number686415
JournalFrontiers in immunology
Volume12
DOIs
StatePublished - Jun 15 2021

Bibliographical note

Funding Information:
Breeding pairs of strain 13 guinea pigs were generously shared by the U.S. Army Medical Research Institute of Infectious Diseases. Next-generation sequencing library generation and Illumina sequencing were completed by the University of Minnesota Genomics Center. Histopathologic studies were supported by Colleen Forster of the University of Minnesota Histology and Research Laboratory, which is supported by the National Institutes of Health?s National Center for Advancing Translational Sciences, grant UL1TR002494, and the resources and staff of the University of Minnesota University Imaging Centers (UIC, SCR_020997). Grants from the National Institutes of Health (R21HD087496 to CB and R01HD098866 to MS) and the Minnesota Masons (Masonic Early Investigator Award to CB) supported this work. The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript.

Funding Information:
Breeding pairs of strain 13 guinea pigs were generously shared by the U.S. Army Medical Research Institute of Infectious Diseases. Next-generation sequencing library generation and Illumina sequencing were completed by the University of Minnesota Genomics Center. Histopathologic studies were supported by Colleen Forster of the University of Minnesota Histology and Research Laboratory, which is supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, grant UL1TR002494, and the resources and staff of the University of Minnesota University Imaging Centers (UIC, SCR_020997). Grants from the National Institutes of Health (R21HD087496 to CB and R01HD098866 to MS) and the Minnesota Masons (Masonic Early Investigator Award to CB) supported this work. The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript.

Funding Information:
This project was supported by grants from the Minnesota Masonic Charities (Masonic Early Investigator Award) and the National Institutes of Health (R21HD087496, R01HD098866, and UL1TR002494).

Publisher Copyright:
© Copyright © 2021 Berkebile, Putri, Abrahante, Seelig, Schleiss and Bierle.

Keywords

  • congenital infection
  • cytomegalovirus
  • fetal membranes
  • guinea pig
  • inflammation
  • placenta

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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