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

控制 B 族链球菌在女性生殖道中持续存在的宿主和细菌机制

• 批准号: 10754833
• 负责人: Kelly S Doran
• 金额: $ 2.98万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-03 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754833
• 关键词: Acute suppurative arthritis due to bacteria; Address; Adherence; Adult; Antigens; Bacteria; Bacterial Adhesins; Bioinformatics; Birth; Cell Communication; Cells; Complex; Contracts; Development; Diabetes Mellitus; Disease; Elderly; Epithelium; Female genitalia; Fetus; Gastrointestinal tract structure; HIV; Host Defense; IL17 gene; Immune; Immune response; Immunity; In Vitro; Infant; Infection; Inflammation; Integration Host Factors; Intermediate Filaments; Invaded; Keratin-19; Malignant Neoplasms; Mediating; Meningitis; Microbe; Modeling; Molecular; Morbidity - disease rate; Mus; Neonatal; Osteomyelitis; Pathogenesis; Play; Pneumonia; Population; Pregnancy; Pregnancy Outcome; Pregnant Women; Premature Birth; Process; Production; Reporter; Research; Risk Factors; Role; Sepsis; Signal Transduction; Streptococcal Infections; Streptococcus; Streptococcus Group B; Surface; System; T-Lymphocyte; Tertiary Protein Structure; Tissues; Toxin; Uterus; Vagina; Vimentin; Woman; adverse pregnancy outcome; amniotic cavity; antagonist; antitoxin; aspirate; commensal microbes; epithelial to mesenchymal transition; host microbiota; immune activation; in vivo Model; intrauterine infection; mortality; neonatal infection; neonate; normal microbiota; pathobiont; placental infection; placental membrane; reproductive tract; response; stillbirth; vaginal fluid; vaginal microbiota

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.

项目 不利 发病率 什么时候 组织 联系 母亲的 (FGT) 可能 概括 妊娠结局，包括早产和死产，是新生儿出生的主要原因 和死亡率。早产和死产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 伴有上行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 持续存在的机制 并上升到子宫仍未知。 GBS 定植状态是间歇性的并且可能是短暂的， 反映 GBS 决定因素、共生菌群的拮抗作用和宿主免疫的组合 , 女性生殖道 回应。当前的提案旨在解决 GBS 阴道携带的这些动态方面，特别是 1) 细菌粘附到 FGT 的宿主细胞/组织，2) 与阴道微生物群竞争，3) 逃避 主机防御。最近的研究表明，GBS 通过以下方式刺激阴道上皮脱落： 激活上皮间质转化 (EMT)，导致屏障功能丧失和 GBS 传播至上层 FGT 和胎儿。我们最近发现了一种 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 急救人员。我们假设当 EMT 被诱导时，BspC-波形蛋白相互作用在 GBS 中发挥重要作用 阴道持续存在和上行感染。我们进一步发现GBS具有VII型分泌物 有助于殖民化的系统（T7SS）。我们假设 T7SS 对于与 阴道微生物群用于建立生态位并分泌可能激发宿主免疫的抗真核毒素 回复。我们还证明了 IL-17A 在 GBS 定植过程中产生，并且 IL-17+ 细胞， 例如 MAIT 和  T 细胞，实际上促进了 GBS 的上行传播。我们假设 白细胞介素17 诱导的 BspC-vimentin 这些假设将在下面讨论 具体目标：AIM 1：阐明 BspC 和中间丝对 GBS 阴道的贡献 持久性，目标 2：检查新发现的 GBS T7SS 在介导阴道生态位中的功能 建立和细菌间竞争，目标 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 内定植和持续存在的因素 新生儿疾病。 IL-17 和 FGT 中产生的 T 细胞会诱导 EMT 和屏障破坏。这就回到了原点。一旦 EMT 作为启动细胞剥落的防御反应，GBS 可能通过 相互作用，以持久存在于 FGT 中。