Fetal inflammation and infcetion remains a major cause of neonatal mortality and morbidity. Our previous studies showed that histological chorioamnionitis (HCA), microbial-driven infiltration of leukocytes to the maternal-fetal interface, was associated with a focal increase in the number of Hofbauer cells (HBCs) (i.e. placental macrophages of fetal origin located beneath the syncytium and adjacent to fetal capillaries), in the placental villus. Elucidation of cell type-specific responses to polymicrobial challenges would lead to new interventions which reduce the incidence of and/or severity of adverse outcomes including fetal-inflammatory response syndrome (FIRS), a multisystemic/microbial-driven inflammation in the umbilical cord (funisitis) and fetus, which is associated with significant neonatal/pediatric mortality and morbidity. Microbial compounds trigger innate immune response through Toll-like receptors (TLRs), and TAMs, a recently characterized subfamily of protein tyrosine kinase receptors shown to inhibit TLR function in non-placental cell types. In addition, inflammatory response to microbes is regulated through the inflammasome, a multi-protein complex. Our central hypothesis is that herpes virus infection of HBCs suppresses their inflammatory responses to bacteria by altering TAM receptor and Nalp3 inflammasome function, thus inhibiting HBCs' ability to control bacterial growth and, therefore, exacerbating placental/fetal infection, and chorioamnionitis.
Our Specific Aims will: 1) Test the hypothesis that herpes virus infection of HBCs blocks LPS-induced TNF-? and IL-1? through modification of the expression and function of TAM receptors and the Nalp3 inflammasome; 2) Test the hypothesis that HV infection of HBCs increases TAM receptor function and inhibits inflammasome activity which promotes the migration and colonization of bacteria to the fetus; 3) Test the hypothesis that a polymicrobial herpes virus-bacterial infection increases placental macrophages with a suppressed inflammatory phenotype in vivo, promoting the migration of bacteria from mother to the fetus.
The findings from this study will help us to understand how polymicrobial infection during pregnancy results in bacterial infection of the fetus, a condition associated with fetal inflammation and significant neonatal mortality and morbidity. Upon completion of this study, the importance of Hofbauer cells (fetal-placental macrophages), a novel understudied cell type, in placental response to a viral-bacterial polymicrobial infection will be identified, relative contributions of fetal vs maternal factors in mediating bacterial proliferation and inflammation will be documented, and a potential intervention to reduce bacterial infection of the fetus, a major sequela of fetal infections and inflammation will be established.