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

工程 不利的 发病率 什么时候 组织 相联 母性 (FGT) 似然 摘要 妊娠结局，包括早产和死产，是新生儿的主要原因。 和死亡率。导致早产和死产的一个常见原因是宫内感染。 细菌从阴道上升到子宫，侵入羊膜腔，导致炎症， 损害和不良妊娠结局。B群链球菌(GBS)就是这样一种细菌 有上升的感染和不良妊娠结局。造成这种情况的主要风险因素是 阴道定植；然而，GBS持续存在于 并上升到子宫仍然是未知的。GBS定植状态是间歇性的并且可以是暂时的， 反映了GBS决定因素、共生菌群的拮抗和宿主免疫的组合 ，女性生殖道 回应。目前的提案旨在解决GBS阴道分娩的这些动态方面，具体而言 1)细菌附着于FGT的宿主细胞/组织，2)与阴道微生物区系竞争，3)逃避 主场防守。最近的研究表明，GBS通过以下方式刺激阴道上皮脱落 激活上皮间充质转化(EMT)，导致屏障功能丧失和GBS 播散到FGT上部和胎儿。我们最近发现了一种GBS表面粘附素，BSPC，它 直接与宿主中间丝相互作用，包括角蛋白19和波形蛋白，这是一种典型的 急诊室。我们推测，当诱发EMT时，BSPC-Vimentin相互作用在GBS中起重要作用 阴道滞留和上行性感染。我们进一步发现GBS有一种VII型分泌物 有助于殖民的系统(T7SS)。我们假设T7SS对于与 用于建立生态位和分泌可激发宿主免疫的抗真核毒素的阴道微生物区系 回应。我们还证明了IL-17A是在GBS定植过程中产生的，并且IL-17+细胞， 例如MAITs和T细胞，实际上促成了GBS的向上扩散。我们假设 IL-17 诱导 BSPC-VIMENTN这些假设将在以下内容中阐述 具体目标：目标1：阐明BSPC和中间丝在GBS阴道中的作用 持续性，目标2：研究新发现的GBS T7SS在调节阴道生态位中的作用 建立和细菌间竞争，目标3：确定IL-17和MAITs对 GBS定植的发病机制。这些研究应该会增加我们对细菌和宿主的了解 影响GBS上升感染和FGT内定植和持久性的因素 新生儿疾病。 IL-17和 在FGT中产生T细胞会导致EMT和屏障的破坏。这又回到了原点；一旦EMT 作为启动细胞脱落的防御性反应，GBS劫持了这一过程，可能是通过 互动，以坚持在FGT。

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.