Determining the contribution of zinc deficiency to perinatal Group B Streptococcus infections

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Project Summary Zinc deficiency is a global problem associated with preterm birth. Zinc supplementation has also been shown to prevent preterm birth, but heterogeneous results of clinical studies suggest that certain, as yet undefined, populations are likely to benefit from zinc more than others. Given the importance of infections as causes of preterm birth, especially in regions affected by micronutrient deficiency, it is possible that low zinc levels contribute to the risk for perinatal infections. However, little is known about this possible relationship. Group B Streptococcus agalactiae (GBS) is a major cause of intrauterine infections during pregnancy, where it can invade amniotic fluid and infect the developing fetus. The risk for perinatal GBS infections is highest in regions where micronutrient deficiency is common. To cause intrauterine infection, GBS must first colonize the vagina, where the low pH stimulates biofilm formation. The vaginal mucosa resists colonization by non-commensal bacteria through a repertoire of antimicrobial molecules including S100A-family proteins (S100A8/A9 and S100A12) that participate in nutritional immunity via zinc chelation. Neutrophils also secrete these proteins at sites of bacterial infection. We have new and exciting data to suggest that zinc deficiency provokes major changes in the behavior of GBS, with strong effects on the formation of biofilms, structures that aid in bacterial persistence in the environment, which we speculate are important for vaginal colonization. Furthermore, we have also discovered that GBS encoded a zinc efflux determinant, CadD, which promotes GBS resistance to zinc intoxication, survival and persistence within macrophages, and ascending infection in a pregnant host. Given this, we hypothesize that zinc deficiency, specifically in the context of pregnancy, leads to an increased risk for vaginal GBS colonization and invasive infection. We will test this by determining the contribution of zinc homeostasis to bacterial-host interactions, investigating the influence of zinc on immunological responses in human gestational membranes and disease progression in a mouse model of invasive GBS infection, and evaluate the impact of zinc homeostasis on GBS colonization in pregnant women. This work will identify novel biomarkers for increased disease risk and cost-effective dietary or chemotherapeutic strategies that could improve pregnancy outcomes.