Cytomegalovirus (CMV) is a persistent pathogen infecting a large proportion of the human population. In the developing fetus and immunocompromised patients, CMV causes significant morbidity and mortality. Mechanisms involved in human cytomegalovirus (HCMV) transmission from mother to child remain unknown. A better understanding of these mechanisms is necessary for development of vaccine against congenital HCMV infection. Recent studies of the institute for medical immunology have shown that mother to child HCMV transmission during pregnancy is associated with a compartmentalized replication of HCMV in genital tract, mammary gland and placenta. These results lead Nicolas Twité and his reserach team to postulate that HCMV immune evasion strategies are organ specific.
The aim of this project is to investigate immune mechanisms involved in the control of HCMV replication in epithelial cells from cervix-vagina, mammary gland and kidney. In vivo study (primary tissues) of immune mechanisms is more complicated in human being but in vitro model of infection is an appropriated alternative. Primary cultures of epithelial cells were infected in vitro with different strains of HCMV. Fibroblasts were used as control in their experiments. Kinetics of viral antigens expression and viral particles production were studied. Impact of infection on immunomodulatory molecules expression (HLA-ABC, HLA-E, HLA-G and E-cadherin) and its influence on phenotypic characteristics and effector functions of Natural Killer cells were investigated. Role of these effector cells in the control of HCMV replication was also analyzed. Nicolas Twité and his research team have shown that human mammary epithelial cells are permissive to productive HCMV infection and viral particles remain bound to the plasma membrane of epithelial cells but not fibroblasts. They have also shown that while HCMV induces in fibroblasts and epithelial cells from kidney and mammary gland a down regulation of HLA-ABC molecules, it induces an up-regulation of HLA-E in mammary and renal epithelial cells and an up-regulation of HLA-G only in renal epithelial cells. They have also shown that HCMV induces an up-regulation of E-cadherin in kidney epithelial cells. These ligands, HLA-E, HLA-G and E-cadherin, interacting with NK inhibitory receptors NKG2A, ILT2/ILT4 and KLRG1 respectively could play an important role in evasion strategies of HCMV to NK cell-mediated cytotoxicity. Moreover, up-regulated HLA-G expression in kidney cells could make effector NK and T cells act as immunosuppressor/regulatory cells. This project should allow them to better understand HCMV immune evasion strategies leading to its transmission throughout the world. This helps them in developing process of vaccine against HCMV.