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.
Highlights
Congenital cytomegalovirus infection, a leading cause of sensorineural hearing loss and neurocognitive disability in children, occurs in roughly 1 in 200 pregnancies [1,2,3]. cCMV is a cause of intrauterine growth restriction, preterm birth, and fetal demise [4,5,6,7,8]
To study how the timing of maternal guinea pig cytomegalovirus (GPCMV) infection affects viral loads in the placenta, extraplacental membranes, and fetus, guinea pigs were time mated during postpartum estrus and infected at either 21 or 35 days gestation (Figure 1)
The timing of Human cytomegalovirus (HCMV) infection during pregnancy is a determinant of fetal outcomes, yet how placental development affects the course and severity of cCMV remains poorly understood [25, 72]
Summary
Congenital cytomegalovirus infection (cCMV), a leading cause of sensorineural hearing loss and neurocognitive disability in children, occurs in roughly 1 in 200 pregnancies [1,2,3]. cCMV is a cause of intrauterine growth restriction, preterm birth, and fetal demise [4,5,6,7,8]. The timing of maternal human cytomegalovirus (HCMV) infection during pregnancy affects the rate of congenital transmission and fetal outcomes post-infection [9,10,11,12,13,14,15,16,17,18]. Maternal infection late in pregnancy is associated with the highest rates of intrauterine growth restriction (IUGR) and congenital infection [9,10,11,12,13, 15, 18]. HCMV infects the placenta and these placental infections can cause fetal injury, including spontaneous abortion and neonatal demise, even in the absence of detectable viral transmission to the fetus [4, 5, 19,20,21,22]. While HCMV appears to cause a hypoxia-like condition in infected placenta, how HCMV causes placental dysfunction remains poorly understood [22]
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