Impact of Maternal Inflammation and Cell Trafficking on Fetal Immune Ontogeny

PROJECT SUMMARY / ABSTRACT These investigations explore the hypothesis that maternal inflammation due to acute or chronic virus infection during pregnancy has a durable impact on the development of the fetal immune system, which is mediated by changes in placental function and transplacental transfer of metabolites and inflammatory mediators to the fetus. Our studies have shown that subclinical rhesus cytomegalovirus (RhCMV) infection during pregnancy is associated with dramatic alterations of immune function in offspring—demonstrating a vertical effect of maternal inflammation on immune system development. Our prior studies have also demonstrated a fetal response that impacts how microglial cells, the resident immune cells of the central nervous system, engage and engulf neural precursor cells. These investigations will probe the link between maternal, placental, and fetal inflammation in a translational primate model system that closely recapitulates human development and disease, and using state-of-the-art tools and technologies through the following Specific Aims: (1) Determine the impact of acute maternal RhCMV infection and consequent inflammation on fetal innate and adaptive immune functions, in seronegative and seropositive dams; (2) Assess the impact of acute and chronic RhCMV infection on the placenta and maternal-fetal cell trafficking; and (3) Test the postnatal consequences of fetal immune development in the context of maternal infection with RhCMV and associated inflammation. The studies proposed are designed to test the hypothesis that maternal, placental, and fetal immune responses contribute to developmental sequelae including alterations in postnatal immunity, providing key insights on a common worldwide maternal and congenital infection.