Polymicrobial Context of Neisseria gonorrhoeae Infection and Mucosal Immune Response

淋病奈瑟菌感染和粘膜免疫反应的多种微生物环境

• 批准号: 10596520
• 负责人: Alison K Criss
• 金额: $ 17.42万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-20 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596520
• 关键词: 3-Dimensional; Address; Affect; Anaerobic Bacteria; Antibiotics; Architecture; Autologous; Bacterial Vaginosis; Biology; Biomimetics; Cells; Cervical; Cervix Uteri; Chlamydia; Chlamydia trachomatis; Communicable Diseases; Communities; Ectopic Pregnancy; Environment; Epidemiology; Epithelium; Exudate; Female; Female genitalia; Gonorrhea; Gram-Negative Bacteria; Health; Host Defense; Human; Immune; Immune response; Immunity; Infection; Infertility; Infiltration; Inflammation; Inflammatory Response; Intervention; Knowledge; Lactobacillus; Microbe; Modeling; Mucosal Immune Responses; Mucous Membrane; Neisseria gonorrhoeae; Neutrophil Infiltration; Outcome; Pathogenesis; Pelvic Inflammatory Disease; Predisposition; Process; Productivity; Public Health; Recommendation; Resistance; Sexually Transmitted Diseases; Structure; System; Time; Tissues; Vaccines; Vagina; Woman; Women' s Health; antimicrobial; cervicovaginal; co-infection; defense response; genital infection; genital microbiota; host microbiota; microbial; microbiome; microbiota; neutrophil; novel therapeutic intervention; pathogen; permissiveness; programs; recruit; reproductive; reproductive fitness; reproductive tract; resistance frequency; response; therapy development; transmission process

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.

项目摘要/摘要 淋病奈瑟氏菌是一种革兰氏阴性细菌，可引起性传播感染（STI） 淋病。估计每年在世界范围内每年有7800万例淋病病例 对所有推荐抗生素的耐药性，以及缺乏保护性疫苗，N。Gono​​rrhoeae是突出的 以及对人类健康的威胁。在女性中，N。Gono​​rrhoeae在子宫颈建立感染 引发以局部嗜中性粒细胞募集为特征的炎症反应。可行的N. Gonorrhoeae 从人淋病的渗出液中回收，表明中性粒细胞无法有效清除感染。 持续感染和嗜中性粒细胞感染的结果循环使淋病的梭菌传播为 以及升高的感染和组织损伤，后遗症（如骨盆炎症性疾病）是 生态妊娠和不育。此外，淋病猪笼草的感染在流行病上高度相关 通过与沙眼衣原体共感染，增强了这些负面后果的可能性。识别 这些突出的STI病原体的宫颈感染和感染的机制对于 寻找新的治疗方法来增强妇女的整体健康和生殖健康。我们的知识 在女性中促进促淋病的细菌和宿主状况，受到女性感染的影响。 没有适合人类生殖器感染的强大模型，该模型融合了居民和招募的宿主细胞， 维持下部女性生殖道的结构，并结合生殖器菌群。克服 在这个知识差距，我们将使用我们小组开发的3D人类主要宫颈阴道仿生系统 回答有关女性生殖器感染生物学的基本问题 我们假设的子宫颈阴道微生物群与易感性有关（细菌阴道相关） 厌氧菌，社区状态IV）和抵抗（乳杆菌crispatus-Dominant，社区国家类型 - 我）。 AIM 1将定义微生物群对卵巢乳杆菌感染的进展的影响 和对上皮宿主防御的影响。 AIM 2将表征微生物群对宫颈阴道的影响 响应淋病猪笼草的募集。 AIM 3将定义如何与Gonorrhoeae N. 在微生物群的背景下，沙眼梭状疱疹会影响病原体伯嫩和宫颈阴道免疫 回复。这些研究将包括女性的阴道和宫颈细胞以及其自体细胞 微生物群以及无与伦比的微生物群，以评估宿主微生物群的相互作用如何影响 感染的进展和结果。这些有关感染过程和 确保炎症反应和组织完整性可以揭示新的干预措施，以限制细菌负荷和 粘膜上皮损害，从而减轻这些常见妇女的负面后果， 衰弱的细菌性传播感染。