Cervicovaginal microbiome, mucosal immunity, and pathogen factors that contribute to spontaneous clearance of Chlamydia trachomatis

宫颈阴道微生物群、粘膜免疫和有助于沙眼衣原体自发清除的病原体因素

• 批准号: 10631994
• 负责人: REBECCA M. BROTMAN
• 金额: $ 77.44万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631994
• 关键词: Adjuvant; Affect; Age; Animals; Anti-Inflammatory Agents; Antibiotic Therapy; Antibiotics; Archives; Bacteria; Bacterial Vaginosis; Behavioral; Biogenic Amines; Biological; Biological Response Modifier Therapy; Cell Adhesion; Characteristics; Chlamydia; Chlamydia trachomatis; Clinical; Costs and Benefits; Data; Development; Dimensions; Ectopic Pregnancy; Epidemiology; Equilibrium; Event; Formulation; Future; Genes; Genital; Genitalia; Guidelines; Health Care Costs; Human; Immune response; Immunity; Immunologic Factors; Immunologics; In Vitro; Incidence; Indoles; Infection; Infertility; Inflammation; Interferon Type II; Interleukin-10; Interleukin-12; Interleukin-2; Interleukin-4; Interleukin-6; Intervention; Irrigation; Isomerism; Kynurenine; Lactic acid; Lactobacillus; Link; Longitudinal Studies; Lubricants; Machine Learning; Metagenomics; Methods; Mission; Modeling; Modernization; Mucosal Immunity; Mucous Membrane; Multiomic Data; Mus; NIH Program Announcements; Natural History; Organism; Outcome; Pathologic; Pelvic Inflammatory Disease; Personal Behavior; Pharmaceutical Preparations; Prevention strategy; Preventive; Prevotella; Proliferating; Recommendation; Recording of previous events; Recurrence; Reporting; Resolution; Resources; Risk; Role; Sampling; Serotyping; Sexually Transmitted Diseases; Smoking; Stress; Structure; System; T-Lymphocyte; Techniques; Th1 Cells; Th2 Cells; Tryptophan; United States National Institutes of Health; Vaccine Research; Vaccines; Vagina; Visit; Woman; Work; antibiotic design; cervicovaginal; cervicovaginal microbiome; chronic pelvic pain; cis-female; clinically relevant; cohort; confirmatory trial; enhancing factor; epidemiology study; experience; follow-up; guinea pig model; high dimensionality; hormonal contraception; human old age (65+); immunoregulation; infection rate; infection risk; inflammatory marker; major outer membrane protein; metabolome; metabolomics; multidisciplinary; novel; novel strategies; pathogen; prevent; programs; repository; response; routine Bacterial stain; sample archive; screening; screening program; successful intervention; vaccine trial; vaginal microbiome; vaginal microbiota; young woman

Chlamydia trachomatis (CT) is the most commonly reported bacterial sexually transmitted infection in the U.S. and untreated infections are a major cause of adverse sequelae, including pelvic inflammatory disease, infertility, and ectopic pregnancy. Screening programs have failed to curb rising infection rates. As most infections in women are asymptomatic and screening is only recommended annually, the incidence of CT is likely higher than reported. While antibiotic therapy is curative, successful biomedical prevention strategies are lacking. Most CT natural history studies evaluate CT in the short 1-2 week interval between screening and follow-up for treatment. Few studies have had longer follow-up. Overall, these studies suggest spontaneous clearance of CT (in the absence of antibiotic treatment) occurs in 11-44% of cases; however, the mechanisms are poorly understood. The vaginal microbiome (VMB) is a major factor in preventing CT acquisition, and the VMB may also aid in CT clearance by reducing CT proliferation and promoting effective immune responses. Thus, identifying modifiable vaginal microenvironmental features that play a role in spontaneous clearance of CT may lead to novel interventions. This proposal is submitted in response to PA-19-096 “Control of Sexually Transmitted Infections (STIs) Through a Comprehensive Understanding of the Natural History of Infection”. We propose to investigate the relations between spontaneous CT clearance and VMB (structure, function, metabolome), mucosal immunity, and CT serovar-specific features. This proposal will utilize archived cervicovaginal lavage samples collected from the Longitudinal Study of Vaginal Flora in which 3,620 cisgender women were followed quarterly for one year. Samples were retrospectively screened for CT after the study concluded and detected CT spontaneous clearance (n=311) and persistence (n=321) events. The specific aims utilize a repository with a long follow-up and will assess four domains that may drive the natural history of CT: 1) demographic, clinical, and behavioral factors, 2) vaginal microbiome and metabolome, 3) mucosal soluble markers of inflammation, 4) CT serovar composition. Our experienced, multi- disciplinary team will adapt, refine, and apply modern methods in longitudinal epidemiology with machine- learning and dimension-reduction techniques to assess high-dimensional, multi-omic data. We seek to identify immunologic, metabolomic, and bacterial candidates that are associated with spontaneous CT clearance. This epidemiologic study of over 600 archived samples presents the best available resource for identifying likely natural clearance and persistence mechanisms. Findings from the analyses would provide the cost-benefit justification for future confirmatory trials and experimental mechanistic studies. The results may lead to new CT vaccine approaches by pinpointing correlates of protection against clinically-relevant serovars and informing choice of adjuvants for optimal immune response. The data may also aid the design of antibiotic-sparing approaches, such as live biotherapeutic formulations, which could enhance CT control programs.

沙眼衣原体 (CT) 是美国最常报告的细菌性传播感染。 未经治疗的感染是不良后遗症的主要原因，包括盆腔炎、 不孕症、宫外孕。筛查计划未能遏制感染率上升。正如大多数 女性感染无症状，仅建议每年进行筛查，CT 发生率 可能比报道的要高。虽然抗生素治疗具有疗效，但成功的生物医学预防策略 缺乏。大多数 CT 自然史研究在筛查和筛查之间的短短 1-2 周间隔内评估 CT 后续治疗。很少有研究进行更长时间的随访。总体而言，这些研究表明自发 11-44% 的病例可通过 CT 检查（在没有抗生素治疗的情况下）；然而，这些机制 人们了解甚少。阴道微生物组 (VMB) 是阻止 CT 采集的主要因素， VMB 还可以通过减少 CT 增殖和促进有效的免疫反应来帮助 CT 清除。 因此，识别在自发清除中发挥作用的可改变的阴道微环境特征 CT 可能会带来新的干预措施。本提案是针对 PA-19-096“控制 通过全面了解性传播感染 (STI) 的自然历史 感染”。我们建议研究自发CT清除率与VMB之间的关系 （结构、功能、代谢组）、粘膜免疫和 CT 血清型特异性特征。该提案将 利用从阴道菌群纵向研究中收集的存档宫颈阴道灌洗样本，其中 每季度对 3,620 名顺性别女性进行为期一年的跟踪调查。对样本进行CT回顾性筛查 研究结束并检测到 CT 自发清除（n=311）和持续性（n=321）后 事件。具体目标利用一个长期跟踪的存储库，并将评估可能驱动的四个领域 CT 的自然史：1) 人口、临床和行为因素，2) 阴道微生物组和 代谢组，3) 炎症粘膜可溶性标志物，4) CT 血清成分。我们经验丰富、多 学科团队将利用机器来调整、完善和应用纵向流行病学的现代方法 用于评估高维、多组学数据的学习和降维技术。我们寻求确定 与自发 CT 清除相关的免疫学、代谢组学和细菌候选物。这 对 600 多个存档样本的流行病学研究提供了识别可能的最佳可用资源 自然清除和持续机制。分析结果将提供成本效益 未来验证性试验和实验机制研究的理由。结果可能会导致新的CT 疫苗方法通过查明针对临床相关血清型的保护的相关性并告知 选择佐剂以获得最佳免疫反应。这些数据还可能有助于抗生素节约的设计 活生物治疗制剂等方法可以增强 CT 控制计划。