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性传播感染。 而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， 不孕不育和异位妊娠。筛查计划未能遏制不断上升的感染率。就像大多数 女性感染无症状，仅建议每年进行筛查，CT的发病率为 可能比报道的要高。虽然抗生素治疗是治愈的，但成功的生物医学预防策略是 缺乏。大多数CT自然病史研究在筛查和检查之间的短短1-2周时间内评估CT 随访治疗。很少有研究有更长的随访时间。总体而言，这些研究表明是自发的 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，其机制 人们对此了解甚少。阴道微生物群(VMB)是阻止CT感染的主要因素，而 VMB还可能通过减少CT的增殖和促进有效的免疫反应来帮助CT清除。 因此，确定可改变的阴道微环境特征在自发清除 CT可能导致新的介入治疗。本提案是为响应PA-19-096《控制 通过对自然历史的全面了解了解性传播感染(STI) 感染的可能性“。我们建议研究自发性CT清除与VMB的关系 (结构、功能、代谢体)、粘膜免疫和CT血清型特有特征。这项提议将 利用从阴道菌群纵向研究中收集的归档宫颈阴道灌洗液样本 3620名顺性女性接受了为期一年的季度跟踪调查。对样本进行回顾性CT筛查 研究结束后检测CT自发清除(n=311)和持续(n=321) 事件。具体的目标利用一个具有长期跟踪的存储库，并将评估可能推动 CT的自然历史：1)人口统计、临床和行为因素，2)阴道微生物组和 代谢体，3)粘膜炎症可溶性标志物，4)CT血清型组成。我们经验丰富的多面手 学科团队将适应、改进和应用现代方法在纵向流行病学中与机器- 学习和降维技术，以评估高维、多组数据。我们试图找出 与自发CT清除相关的免疫学、代谢学和细菌候选。这 对600多个存档样本进行的流行病学研究提供了确定疑似 自然清除和持久机制。分析结果将提供成本效益 为未来的验证性试验和实验机制研究提供理由。这一结果可能会导致新的CT 疫苗方法，通过确定针对临床相关血清型的保护相关因素并告知 选择最佳免疫反应的佐剂。这些数据也可能有助于抗生素节约的设计 方法，如活的生物治疗制剂，可以加强CT控制程序。