HCMV inhibition of cytotrophoblast differentiation through dysregulation of Wnt/?

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DESCRIPTION (provided by applicant): Human Cytomegalovirus (HCMV) is a ubiquitous herpesvirus that currently infects a large percentage of the world population. Although usually asymptomatic in immunocompetent individuals, HCMV infection during pregnancy may cause spontaneous abortions, premature delivery, or permanent neurological disabilities in infants infected in utero. In many cases, it is the placenta, not the embryo or fetus that shows evidence of infection. Recent studies have demonstrated that HCMV infection inhibits cytotrophoblast (CTB) invasion resulting in shallow placentation. The overall goal of the proposed studies proposed is to determine the molecular mechanism(s) by which HCMV impairs CTB invasion during placentation. During infection, the virus exerts control over a multitude of host signaling pathways. Our preliminary data show that the transcriptional activity of ¿-catenin is significantly inhibited in HCMV infected CTBs. ¿-catenin is the key factor in the canonical Wnt/¿-catenin signaling pathway that has recently been shown to be critical for invasive differentiation of CTBs during placentation; however, the effect of HCMV on this pathway is unknown. The hypothesis to be tested is that HCMV inhibits CTB differentiation and function through dysregulation of canonical Wnt/¿-catenin signaling. Aim 1 will employ an innovative in vitro model of placental trophoblast differentiation employing newly discovered human primary trophoblast progenitor cells (TBPCs) and rotating wall vessel (RWV) bioreactor technology in order to determine the effect of HCMV infection on early and late stages of trophoblast differentiation and demonstrate the importance of canonical Wnt/¿-catenin signaling during TBPC differentiation, and the effect of HCMV infection on Wnt/¿-catenin signaling. Aim 2 will define the molecular crosstalk between peroxisome proliferator-activated receptor gamma (PPAR?) and ¿-catenin pathways during CTB differentiation. PPAR? has been shown to control trophoblast invasion and differentiation, as well as negatively regulate ¿-catenin. The transcription factor E2F1 that is activated by HCMV UL97 is postulated to be key to the convergent regulation of these pathways. An understanding of the mechanisms underlying dysregulation of Wnt/¿-catenin signaling following infection of CTBs by HCMV may provide new prognostic and therapeutic approaches to reduce the risks of congenital infection and prevent complications during pregnancy.