Mechanisms regulating fetal membrane and neutrophil responses to polymicrobial infection

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Chorioamnionitis is a major risk factor for spontaneous preterm birth and a leading contributor to poor fetal and neonatal outcomes. Chorioamnionitis, defined as inflammation of the fetal membranes (FM), is usually subclinical and diagnosed as histological chorioamnionitis (HCA) after delivery, by evidence of neutrophil infiltration. HCA and preterm birth are thought to be initiated by bacterial infection. However, no single bacterium has been attributed to preterm birth, and antibiotic intervention has proven unsuccessful. Moreover, identifiable bacteria associated with HCA and preterm birth are normally present in the female reproductive tract. Thus, another trigger may be responsible. We postulate that one possible risk factor is a viral infection. In preliminary studies we show that a herpes viral infection of human FMs augments their inflammatory response to low-dose bacterial LPS. Thus, we postulate that a viral infection during pregnancy may change the way FMs respond to bacteria normally present in the genital tract, giving rise to aggravated inflammation; and the mechanisms likely involve innate immune Toll-like receptors (TLRs) and their regulators. In preliminary studies found that FMs express functional TAM tyrosine kinase receptors, a novel family of negative regulators that inhibit TLR-driven immune responses and regulate cell survival. Thus, our central hypothesis is that a polymicrobial viral-bacterial infection of the FMs increases a woman's risk for HCA and preterm birth, and this is mediated by changes in the crosstalk between FM TLRs and TAM receptors. Our goals are to understand the mechanisms by which TLRs and TAM receptors function in FMs and neutrophils in response to a polymicrobial infection, and to characterize their role in HCA and preterm birth. We will address major gaps in our knowledge, such as the impact a viral-bacterial polymicrobial infection has on: 1) FM TLR-mediated responses; 2) FM TAM receptor function; and 3) neutrophil survival and function. Our studies will be translational by determining if TAM receptor agonists can reverse polymicrobial-induced FM inflammation and improve pregnancy outcome, and whether they can serve as biomarkers. Since viral pandemics are likely to become more common, and women are at increasing risk for sexually transmitted infections, our studies are critical for guiding the management of pregnant women under these conditions. Our outcomes have the potential of defining new mechanisms of pathology, predictors of prematurity, and therapeutic targets. We will use herpes and influenza viruses as models that may inform us about how other viruses impact pregnancy. Thus, our specific aims are to determine: 1. The role of TAM receptors and the inflammasome in regulating viral sensitization of FMs to bacteria. 2. The impact a polymicrobial FM infection has on neutrophil survival and function. 3. Whether TAM receptor agonists can predict or prevent polymicrobial infection-induced FM inflammation and preterm birth.