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

项目 不良 发病率 当 组织 关联 产妇 （FGT） 可能 总结 妊娠结局，包括早产和死胎，是新生儿死亡的主要原因。 and mortality.早产和死胎的常见原因是宫内感染， 细菌从阴道上升到子宫并侵入羊膜腔，导致炎症， 损害和不良妊娠结局。B族链球菌（GBS）就是这样一种细菌 会导致上行感染和不良妊娠结局主要的风险因素是 阴道定植;然而，GBS在阴道中持续存在的机制 并上升到子宫仍然未知。GBS定殖状态是间歇性的并且可以是短暂的， 反映了GBS决定因素、植物植物群的拮抗作用和宿主免疫 女性生殖道 应答目前的建议旨在解决GBS阴道携带的这些动态方面，具体来说， 1)细菌粘附于FGT的宿主细胞/组织，2）与阴道微生物群竞争，和3）逃避 宿主防御最近的研究表明，GBS刺激阴道上皮脱落， 激活上皮-间质转化（EMT），导致屏障功能丧失和GBS 播散至上FGT和胎儿。我们最近发现了GBS表面粘附素BspC， 直接与宿主中间丝相互作用，包括角蛋白19和波形蛋白，波形蛋白是一种典型的 急救员我们推测，当EMT被诱导时，BspC-波形蛋白相互作用在GBS中起重要作用 阴道残留和上行感染。我们进一步发现GBS有一种VII型分泌物 系统（T7 SS），有助于殖民化。我们假设，T7 SS是重要的竞争， 阴道微生物群用于建立生态位并分泌可引起宿主免疫的抗真核毒素 反应我们还证明了IL-17 A在GBS定殖期间产生，并且IL-17+细胞， 如MAIT和巨噬细胞T细胞，实际上有助于GBS的上升传播。我们假设 IL-17 诱导 BspC-波形蛋白这些假设将在下文中阐述。 目的1：阐明BspC和中间丝在GBS阴道中的作用 持续性，目的2：检查新发现的GBS T7 SS在介导阴道龛中的功能 建立和细菌间竞争，AIM 3：确定IL-17和MAIT对细菌间竞争的贡献。 GBS定植的发病机制。这些研究应该增加我们对细菌和宿主的了解。 影响GBS上行感染的FGT内定植和持久性的因素， 新生儿疾病 IL-17和 FGT中产生的T细胞诱导EMT和屏障破坏。这是一个完整的循环;一旦EMT 作为启动细胞脱落的防御反应，GBS可能通过 互动，在FGT中持续存在。

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.