DESCRIPTION (provided by applicant): Infection with Listeria monocytogenes by contaminated food is a significant public health threat in vulnerable populations. Infection of pregnant women is 20-fold higher than the general population, and there is significant risk for miscarriage, fetal demise, and neonatal infection. While experimental infection is not feasible in pregnant women, the close similarities in the physiology, morphology and immunology of the rhesus monkey and human maternal-fetal interface make the rhesus an outstanding opportunity for translational research in infection and adverse pregnancy outcomes. Supported by in vivo pilot data with infection in pregnant monkeys, we hypothesize that in maternal infection with L. monocytogenes, transmission to the fetus is preceded by decidual infection, decidual and placental inflammation, and damage to decidual vessels and placental integrity. Furthermore, activation of reproductive tract-specific leukocytes precedes tissue pathology, and maternal immune protection is compromised at the maternal-fetal interface. To test these hypotheses we have set three Specific Aims: Specific Aim 1. To test the hypothesis that L. monocytogenes infection in rhesus monkeys is associated with decidual infection, decidual immune cell activation, and deleterious inflammatory vascular events in early pregnancy. Specific Aim 2. To test the hypothesis that adverse pregnancy outcomes are related to the infectious dose of Listeria in early rhesus gestation. Specific Aim 3. To test the hypothesis that pregestational infection in rhesus monkeys fails to protect the maternal-fetal interface with reinfection in subsequent pregnancy. Listeria monocytogenes is an ideal organism to probe the impact of decidual and placental infection on miscarriage and adverse pregnancy outcomes. With well-defined cellular pathogenesis and a wide range of molecular tools available, it provides an outstanding model of intracellular pathogen impact on the maternal- fetal interface. These studies will also establish paradigms for combinatorial studies with other infectious, metabolic, toxicological and endocrine stressors that impact on fetal programming in the intrauterine environment. The collective expertise of the investigators in reproductive biology, microbial pathogenesis and immunology will synergize to move the field forward by establishing a novel and innovative approach with the rhesus monkey to address critical questions in human infection, which include the route by which the placenta is infected in vivo, the nature of the locl immunological response within the decidua to Listeria infection, and the role of a decidual immunological/inflammatory response in pregnancy loss and stillbirths.

PUBLIC HEALTH RELEVANCE: Listeria monocytogenes is a bacterial organism which frequently contaminates the human food supply, particularly processed meats, soft cheeses and unpasteurized milk products. Infection in pregnant women causes miscarriage, stillbirth, preterm labor and neonatal infection. There is a gap in our understanding of mechanisms by which fetal loss occurs, and thus a lack of understanding of ways to address the risk which listeriosis poses for the community. This proposal will use the rhesus monkey provide a deeper understanding of the outcomes of maternal infection, defining responses among uterine immune cells, novel vascular inflammatory changes, and the risk that infection in early gestation poses for pregnancy loss. We will also provide definitive information on the impact of pregestational infection in sensitizing the maternal immune system to respond in a way which may be detrimental to pregnancy success, which is relevant for Listeria as a vaccine vector.