Polymicrobial Context of Neisseria gonorrhoeae Infection and Mucosal Immune Response

项目摘要/摘要 淋球菌是引起性传播感染(STI)的革兰氏阴性细菌。 淋病。据估计，全世界每年有7800万淋病病例，越来越频繁的 对所有推荐的抗生素都有耐药性，而且缺乏保护性疫苗，淋病奈瑟菌是突出的 对人类健康的威胁与日俱增。在女性中，淋球菌在宫颈建立感染，在那里它 启动炎症反应，其特征是中性粒细胞在局部募集。活性淋病奈瑟菌 从人类淋病渗出物中恢复，表明中性粒细胞不能有效清除感染。 由此产生的持续感染和中性粒细胞炎症的循环使淋病奈瑟菌传播成为 以及上升的感染和组织损伤，这是盆腔炎等后遗症的基础， 宫外孕和不孕症。此外，感染淋病奈瑟菌在流行病学上也有很高的关联性。 与沙眼衣原体合并感染，增加了出现这些负面后果的可能性。识别 这些重要的性传播感染病原体引起的宫颈感染和炎症的机制对 寻找新的治疗方法，以提高妇女的整体健康和生殖健康。我们的知识 促进妇女感染淋病奈瑟菌的细菌和宿主条件 缺乏将常驻和招募的宿主细胞结合在一起的强大的人类生殖器感染模型， 维持下部女性生殖道的结构，并包含生殖器微生物区系。要克服 在这一知识空白的情况下，我们将使用本课题组开发的3D人体原代宫颈阴道仿生系统 回答关于女性生殖器感染生物学的基本问题，单独和在 我们假设的宫颈阴道微生物群与易感性(细菌性阴道病相关)相关 厌氧菌，群落状态IV型)和抗性(卷曲乳杆菌占优势，群落状态类型- i)。目的1确定微生物区系对宫颈阴道淋球菌感染进展的影响。 以及对上皮性宿主防御的影响。目标2将描述微生物区系对宫颈阴道的影响 对淋病奈瑟菌免疫细胞的募集。目标3将定义如何与淋病奈瑟菌混合感染 和沙眼衣原体在微生物区系背景下影响病原体负担和宫颈阴道免疫 回应。这些研究将包括来自女性的阴道和宫颈内细胞以及她们的自体 微生物区系，以及不匹配的微生物区系，以评估宿主-微生物区系相互作用如何影响 感染的进展和结果。这些研究的结果是关于感染过程和 随后的炎症反应和组织完整性可以揭示限制细菌负荷和组织完整性的新干预措施 粘膜上皮损伤，从而减轻这些常见的和女性的负面后果 使人衰弱的细菌性传播疾病。

PROJECT SUMMARY/ABSTRACT Neisseria gonorrhoeae is a Gram-negative bacterium that causes the sexually transmitted infection (STI) gonorrhea. With an estimated 78 million cases of gonorrhea annually worldwide, increasing frequency of resistance to all recommended antibiotics, and the lack of a protective vaccine, N. gonorrhoeae is a prominent and growing threat to human health. In women, N. gonorrhoeae establishes infection at the cervix, where it initiates an inflammatory response characterized by the local recruitment of neutrophils. Viable N. gonorrhoeae are recovered from human gonorrheal exudates, indicating that neutrophils cannot effectively clear infection. The resulting cycle of sustained infection and neutrophilic inflammation enables N. gonorrhoeae transmission as well as ascending infection and tissue damage, which underlie sequelae such as pelvic inflammatory disease, ectopic pregnancy, and infertility. Moreover, infection with N. gonorrhoeae is highly epidemiologically associated with coinfection with Chlamydia trachomatis, enhancing likelihood of these negative consequences. Identifying the mechanisms underlying cervical infection and inflammation by these prominent STI pathogens is critical for finding new therapeutic approaches to enhance women’s overall health and reproductive fitness. Our knowledge of the bacterial and host conditions that facilitate productive N. gonorrhoeae infection in women is hampered by the absence of a robust model for human genital infection that incorporates resident and recruited host cells, maintains the architecture of the lower female genital tract, and incorporates the genital microbiota. To overcome this knowledge gap, we will use the 3D human primary cervicovaginal biomimetic system developed by our group to answer fundamental questions about the biology of female genital infection, alone and in the context of cervicovaginal microbiota that we hypothesize are associated with susceptibility (bacterial vaginosis-associated anaerobes, community state type-IV) and resistance (Lactobacillus crispatus-dominant, community state type- I). Aim 1 will define the influence of the microbiota on the progression of cervicovaginal N. gonorrhoeae infection and effects on epithelial host defenses. Aim 2 will characterize the effect of the microbiota on the cervicovaginal recruitment of immune cells in response to N. gonorrhoeae. Aim 3 will define how coinfection with N. gonorrhoeae and C. trachomatis in the context of the microbiota impacts pathogen burden and cervicovaginal immune response. These studies will include vaginal and endocervical cells from women along with their autologous microbiota, as well as unmatched microbiota, to evaluate how the host-microbiota interaction influences the progression and outcome of infections. The findings arising from these studies about the infection process and ensuing inflammatory response and tissue integrity can reveal new interventions to limit bacterial load and mucosal epithelial damage, thereby mitigating the negative consequences in women of these common and debilitating bacterial STIs.