CMV infection impact on placental immunometabolism and fetal immunity

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PROJECT SUMMARY/ABSTRACT Cytomegalovirus (CMV) is a ubiquitous species-specific betaherpesvirus that results in life-long persistent asymptomatic infection in an immunocompetent host. Human CMV (HCMV) is the most common infectious cause of congenital infection, complicating 40,000 births in the U.S. annually. In utero CMV transmission occurs in 33-50% of pregnant CMV-seronegative women with primary infection; it also occurs after non-primary infection in pregnant CMV-seropositive women so that regions of high CMV seroprevalence account for a major part of the global burden of congenital CMV. Studies in mice and humans have shown that CMV has profound effects on both the innate and adaptive immune system. However, there is a gap in knowledge of when CMV imprints the immune system and whether maternal CMV infection during pregnancy can affect fetal development and immunity even in the absence of CMV transmission. In this grant, our aim is to study the effect of maternal exposure to CMV infection on fetal immunity using a biologically relevant rhesus macaque nonhuman primate (NHP) animal model of HCMV. We hypothesize that maternal exposure to CMV infection during pregnancy induces perturbation of cellular metabolism that adversely affect immune cell populations utilizing common metabolic pathways, leading to (i) hitherto unrecognized impact of CMV-mediated metabolic dysregulation on innate and adaptive immunity at the maternal-fetal interface, and (ii) epigenetic modifications and functional effects on fetal T and B lymphocytes, monocytes and NK cells. We will utilize a combined approach of cellular immunology assays, transcriptomics and metabolomics to investigate the effect of CMV infection on placental immunometabolism and fetal immunity in the NHP model. Our specific aims are: #1. To investigate the effect of chronic maternal CMV infection on placental immunometabolism and fetal immunity; and #2. To determine the effect of experimental primary CMV infection during pregnancy on placental immunometabolism and fetal immunity.