HCMV infection of human placental trophoblast progenitor cells: Analysis of differentiation, proliferation and fate determinants

• Applicant: Dr. Martin Zydek
• Subject Area: Gynaecology and Obstetrics ; Virology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 225607933

Human cytomegalovirus (HCMV) is the leading cause of congenital infection and affects 0.5%-1% of births in Western Europe and 1%-3% in the USA. The risk of transplacental transmission upon primary maternal infection in the first trimester of pregnancy is high (40-50%) leading to permanent birth defects in 15% of diseased newborns. The molecular mechanisms that govern congenital HCMV infection and disease are unknown, mainly because of the virus¿ strong species specificity, which precludes the infection of animal models. Known is that HCMV infects the human placenta and dysregulates development, resulting in functional defects that reduce transport of substances to the fetus.I hypothesize that HCMV-induced placental pathology is a consequence of developmental defects from inhibition of differentiation of villous cytotrophoblasts, also referred to as trophoblast progenitor cells (TBPCs). Human TBPCs were recently established at the University of California San Francisco, which now makes it possible to investigate HCMV¿s effects on TBPC differentiation, proliferation and cell fate determination in the human system for the first time. Supporting my above hypothesis, preliminary data reveal that human TBPCs are permissive for a pathogenic clinical HCMV strain and that infection dysregulates key proteins, which have been shown to be involved in trophoblast cell fate determination in mice.Here, I propose to study whether HCMV dysregulates the differentiation, proliferation and cell fate determination of human TBPCs and to elucidate the underlying molecular mechanisms. Furthermore, in a translational approach, I also propose to investigate whether infection of TBPCs and HCMV-induced effects can be prevented by the application of novel human anti-HCMV antibodies.Specific aims of these studies are:1.) Determination of differentiation stage of infected TBPCs as compared with uninfected cells by the analysis of the stage-specific differentiation markers expressed.2.) Investigation of HCMV¿s effects on TBPC proliferation, cell cycle and the expression of cell cycle regulators, such as cyclins and checkpoint kinases.3.) Analysis of HCMV¿s effects on the expression of key regulators of TBPC cell fate.4.) Application of novel human anti-HCMV antibodies to diminish viral effects on differentiation, proliferation and cell fate determination of TBPCs.The results of this project will shed light on the molecular mechanisms that impact placental development in congenital HCMV infection and possibly indicate new therapeutic strategies.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Leonore Pereira