Understanding cytomegalovirus-mediated placental injury

Abstract

Human cytomegalovirus (HCMV), a ubiquitous beta-herpesvirus, is the most common congenital viral infection and leading infectious-disease cause of adverse pregnancy outcomes, including intrauterine growth restriction, fetal demise, and neurocognitive disability in congenitally-infected children. HCMV in utero transmission and pathogenesis remains poorly understood. Two potential mechanisms explaining congenital transmission and placental pathogenesis currently exist: direct infection of placental cells leading to placental injury and virion release into fetal circulation, and inflammatory immune response to viral infection damaging the barrier between maternal and fetal circulation, thereby allowing viral transmission. Here I describe investigation into both mechanisms. Prior studies have demonstrated HCMV directly infects some trophoblasts, the cell class functioning as the physical and immune barrier between maternal and fetal circulation. It has been proposed that HCMV disrupts early placental development by interfering with the maintenance and differentiation of trophoblasts, but the lack of a human trophoblast stem cell (TSC) model has hindered this investigation. Here, I investigate HCMV infection dynamics in a recently isolated TSC line, and report TSCs and TSC-derived cells can be infected by HCMV, but do not support replication. Examination of viral and host gene expression patterns in TSCs revealed viral gene expression was occurring, but was dysregulated. TSC response to viral infection did not demonstrate typical antiviral gene expression patterns, but instead constitutively expressed a select set of antiviral genes regardless of infection status. Additionally, HCMV infection caused dysregulation of gene expression patterns in TSC-derived trophoblasts, indicative of improper differentiation. Primary pathogenic infection at the maternal-fetal interface can cause aberrant CD8+ T cell responses that injure placental tissues and cause fetal demise. Prior research has demonstrated CMV infection in a guinea pig model of pregnancy upregulates T cell recruitment cytokines around infection foci, which may drive T cell-based placental damage and HCMV congenital transmission. To investigate this, I utilized novel monoclonal antibodies specific to guinea pig CD4 and CD8 to deplete T cells in non-pregnant and pregnant guinea pigs during guinea pig CMV infection. CD4+ T cell depletion caused exacerbated disease in both non-pregnant and pregnant guinea pigs, and significantly increased the rate and scale of congenital viral infection. In contrast, α-CD8 treatment depleted CD8+ T cells but had minimal effect on disease, adult and fetal viral loads, and congenital transmission. Depletion did not demonstrated variation in placental pathology. Overall, these findings contribute to better understanding of HCMV placental pathogenesis and congenital transmission mechanisms, and provide further evidence guiding potential vaccine and therapeutic development.