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: 10463072
• 负责人: REBECCA M. BROTMAN
• 金额: $ 79.85万
• 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/10463072
• 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; Hormonal; Human; Immune; 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; Lead; 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; Play; Prevention strategy; Preventive; Prevotella; Recording of previous events; Recurrence; Reporting; Resolution; Resources; Risk; Role; Sampling; Serotyping; Sexually Transmitted Diseases; Smoking; 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; immunoregulation; infection rate; 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）是美国最常见的细菌性传播感染。 未经治疗的感染是导致不良后遗症的主要原因，包括盆腔炎， 不孕和宫外孕。筛查计划未能遏制感染率的上升。因为大多数 女性感染无症状，仅建议每年进行筛查，CT的发病率为 可能比报告的要高。虽然抗生素治疗是治愈性的，但成功的生物医学预防策略 缺乏大多数CT自然史研究在筛选和治疗之间的1-2周间隔内评价CT。 随访治疗。很少有研究有更长的随访时间。总的来说，这些研究表明， CT的清除（在没有抗生素治疗的情况下）发生在11-44%的病例中;然而， 我们对此知之甚少。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应答来帮助CT清除。 因此，确定在自发清除中起作用的可改变的阴道微环境特征， CT可能导致新的干预措施。本提案是根据PA-19-096“控制 性传播感染（STIs）通过全面了解自然史 感染”。我们建议研究自发CT清除和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。这项建议会 利用从阴道植物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名顺性别妇女进行为期一年的跟踪调查。对样本进行回顾性CT筛查 研究结束后，检测到CT自发清除（n=311）和持续性（n=321） 事件具体目标利用一个长期跟踪的知识库，并将评估可能推动 CT的自然史：1）人口统计学、临床和行为因素，2）阴道微生物组， 代谢组，3）粘膜可溶性炎症标志物，4）CT血清型组成。我们经验丰富的，多- 学科团队将适应，完善和应用现代方法在纵向流行病学与机器， 学习和降维技术来评估高维，多组学数据。我们试图找出 免疫学、代谢组学和细菌候选物与自发CT清除相关。这 对600多个存档样本的流行病学研究为确定可能的 自然清除和持久性机制。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。结果可能导致新的CT 通过精确定位临床相关血清型的保护相关因素， 选择最佳免疫应答的佐剂。这些数据还可以帮助设计防腐蚀的 这些方法，如活的生物制剂，可以增强CT控制程序。