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）是美国最常见的细菌性传播感染 未经治疗的感染是后遗症不良后遗症的主要原因，包括盆腔炎症性疾病， 不育和生态妊娠。筛查计划未能遏制感染率上升。大多数 女性的感染是不对称的，仅建议每年进行筛查，CT的事件为 可能高于报道。尽管抗生素疗法是治愈性的，但成功的生物医学预防策略是 缺乏。大多数CT自然史研究在筛选和之间的短短1-2周间隔中评估CT 后续治疗。很少有研究更长的随访。总体而言，这些研究表明赞助 在11-44％的病例中，CT的清除（在没有抗生素治疗的情况下）发生；但是，机制 知之甚少。阴道微生物组（VMB）是防止CT获取的主要因素，并且 VMB还可以通过减少CT增殖并促进有效的免疫回应来帮助CT清除。 这是识别可修改的阴道微环境特征 CT可能会导致新的干预措施。该建议是根据PA-19-096提交的 通过对自然历史的全面理解，性传播感染（ETI） 感染”。我们建议研究赞助CT清除与VMB之间的关系 （结构，功能，代谢组），粘膜免疫学和CT血清特异性特征。该提议将 利用从阴道菌群的纵向研究中收集的存档宫颈阴道灌洗样品，其中 每季度每季度跟踪3,620名Cisgender妇女。回顾性筛选样品中的CT 研究结束后，结束并检测到了CT的致命清除率（n = 311）和持久性（n = 321） 事件。具体目的是利用较长随访的存储库，并将评估可能驱动的四个域 CT的自然历史：1）人口统计学，临床和行为因素，2）阴道微生物组和 代谢组，3）炎症的粘膜固体标记，4）CT血清组成。我们的经验，多 纪律团队将通过机器适应，完善和应用现代方法在纵向流行病学中 学习和减少维度的技术，以评估高维多摩尼克数据。我们试图确定 与赞助CT清除相关的免疫学，代谢组和候选细菌。这 超过600个存档样品的流行病学研究提供了最佳的可用资源，用于识别可能 自然清除和持久机制。分析的发现将提供成本效益 为将来的确认试验和实验机械研究的理由。结果可能会导致新的CT 通过确定针对临床相关血清的保护并告知疫苗的方法 选择最佳免疫反应的调节器。数据还可能有助于设计抗生素 方法，例如实时生物治疗公式，可以增强CT控制程序。