Host and bacterial mechanisms governing Group B streptococcal persistence in the female genital tract

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PROJECT Adverse morbidity when tissue associated maternal (FGT) likely SUMMARY pregnancy outcomes, including premature birth and stillbirth, are the leading causes of neonatal and mortality. A frequent cause of preterm birth and stillbirth is intrauterine infection, which occurs bacteria ascend from the vagina into the uterus and invade the amniotic cavity, leading to inflammation, damage, and adverse pregnancy outcomes. Group B Streptococcus (GBS) is one such bacterium with ascending infection and adverse pregnancy outcomes. The principal risk factor for this is vaginal colonization; however the mechanisms by which GBS persist i n the and ascend to the uterus remain unknown. GBS colonization status is intermittent and can be transient, reflecting a combination of GBS determinants, antagonism by commensal flora, and host immune , female genital tract responses. The current proposal seeks to address these dynamic aspects of GBS vaginal carriage, specifically 1) bacterial adherence to host cells/tissue of the FGT, 2) competition with vaginal microbiota, and 3) evasion of host defense. Recent studies have demonstrated that GBS stimulates vaginal epithelial exfoliation by activating epithelial-to-mesenchymal transition (EMT), leading to loss of barrier function and GBS dissemination to the upper FGT and fetus. We have recently discovered a GBS surface adhesin, BspC, that directly interacts with host intermediate filaments, including keratin 19 and vimentin, a canonical marker of EMT. We hypothesize that when EMT is induced the BspC-vimentin interaction plays an important role in GBS vaginal persistence and ascending infection. We have further discovered that GBS has a type VII secretion system (T7SS) that contributes to colonization. We hypothesize that T7SS is important for competition with vaginal microbiota for niche establishment and secreting anti-eukaryotic toxins that may invoke a host immune response. We have also demonstrated that IL-17A is produced during GBS colonization and that IL-17+ cells, such as MAITs and  T cells, actually contributed to GBS ascending spread. We hypothesize that IL-17 induced BspC-vimentin These hypotheses will be addressed in the following specific aims: AIM 1: Elucidate the contribution of BspC and intermediate filaments to GBS vaginal persistence, AIM 2: Examine the function of newly discovered GBS T7SS in mediating vaginal niche establishment and inter-bacterial competition, AIM 3: Determine the contribution of IL-17 and MAITs to the pathogenesis of GBS colonization. These studies should increase our understanding of the bacterial and host factors involved in the colonization and persistence within the FGT that impact GBS ascending infection and neonatal disease. IL-17 and producing T cells in the FGT induce EMT and barrier breakdown. This comes full circle; Once EMT is as a defensive response to initiate cellular exfoliation, GBS hijacks this process, possibly through a interaction, to persistent in the FGT.