Defining Chlamydia trachomatis adhesion factor epitope-specific antibody responses, functionality, and roles in protection against urogenital infection

定义沙眼衣原体粘附因子表位特异性抗体反应、功能和在预防泌尿生殖道感染中的作用

• 批准号: 10543490
• 负责人: Amanda L Collar
• 金额: $ 3.32万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-18 至 2023-09-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543490
• 关键词: Acute; Adhesions; Affect; Age; Agreement; Animal Model; Animals; Antibiotic Therapy; Antibodies; Antibody Response; Antibody Specificity; Antibody-mediated protection; Antigens; B-Lymphocyte Epitopes; B-Lymphocytes; Bacteriophages; Binding; Biological Models; Biology; CD4 Positive T Lymphocytes; Cells; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Coupled; Ectopic Pregnancy; Eligibility Determination; Epitopes; Fellowship; Female; Future; Genitourinary System Infection; Genitourinary system; Goals; High Prevalence; Human; Immune response; Immunity; Immunize; Immunodominant Epitopes; In Vitro; Infection; Infertility; Investigation; Knowledge; Maps; Mediating; Medical; Modeling; Monitor; Morbidity - disease rate; National Institute of Allergy and Infectious Disease; Nature; New Zealand; Oryctolagus cuniculus; Outcome; Pathology; Patients; Pelvic Inflammatory Disease; Phage Display; Play; Prevalence; Proteins; Recording of previous events; Reporting; Research; Resolution; Role; Serum; Sexually Transmitted Diseases; Specificity; Surface; Techniques; Technology; Testing; Time; United States; Vaccination; Vaccine Design; Vaccines; Virus-like particle; Woman; World Health Organization; antigen test; cohort; experience; follow-up; immunogenic; in vitro activity; in vivo; in vivo Model; interest; major outer membrane protein; medical complication; mouse model; natural antibodies; neutrophil; new technology; novel; pre-clinical; reproductive; reproductive tract; screening program; success; transmission process; tubal infertility; vaccine development; vaccine trial

PROJECT SUMMARY Chlamydia trachomatis (Ct) is the most common bacterial sexually transmitted infection worldwide and causes serious medical complications in women, including pelvic inflammatory disease, ectopic pregnancy, and infertility. Therefore, a vaccine is urgently needed. One obstacle to successful vaccine development is a lack of a comprehensive understanding of the protective immune response to Ct infection, including the role of epitope-specific antibodies. The overall objective of this fellowship proposal is to finely map the antibody response in women with an acute history of Ct infection, determine immunodominant epitopes of Ct antigens, investigate differential antibody responses between women with a positive Ct infection outcome (defined as no Ct reinfection at 3-months follow-up or spontaneous resolution of Ct infection without antibiotic treatment) and women who experience Ct reinfection, and determine the functionality and protective capacity of these antibody responses. The central hypothesis to be tested is that antibody responses will differ between patients who had a positive Ct infection outcome than those who experienced a reinfection of Ct and that these epitope- specific antibodies to adhesion factors of Ct will play an important role in protection (binding to Ct-infected cells, neutralization, antibody-mediated neutrophil killing, and protection from a Ct challenge in murine models). The long-term goal is to inform vaccine design through better understanding of protective immune responses, culminating in an effective Ct vaccine. The following specific aims will be used to test the hypothesis: Specific Aim 1: Define the natural serum antibody response to urogenital Ct infection in women. Utilizing Deep Sequence-Coupled Biopanning, a novel technology that uses a small amount of human sera to finely map the antibody response at an epitope-level, I will elucidate the natural antibody response to Ct infection. This will empirically determine immunodominant epitopes and B cell epitopes to 24 Ct antigens. I will also define differential antibody responses between women who experienced a positive Ct infection outcome compared to those who experienced a Ct reinfection within 3-months of antibiotic treatment. Specific Aim 2: Investigate Ct adhesion factor epitope-specific antibody functions. Antibodies to immunodominant epitopes and differential antibody response between patient cohorts (SA1) will be tested for functionality to determine protective capacity against Ct infection. Using in vitro techniques, I will determine if these epitope-specific antibodies can bind to Ct, have neutralizing capacity, and can function in antibody- mediated neutrophil Ct killing. I will also determine if these antibodies can protect against a Ct infection in a murine model by monitoring Ct infection, bacterial shedding, Ct clearance, and upper genital tract pathology. Together, this proposal will investigate the specificity, functionality, and role of epitope-specific antibodies in protection against Ct infection and has the potential to significantly advance the Ct field by understanding protective immune responses and informing future vaccine design.

项目摘要 沙眼衣原体（CT）是全世界最常见的细菌性传播感染和原因 女性严重的医疗并发症，包括骨盆炎性疾病，异位妊娠和 不育。因此，迫切需要一种疫苗。成功开发疫苗的一个障碍是缺乏 对CT感染的保护性免疫反应的全面理解，包括 表位特异性抗体。该奖学金提案的总体目的是精细绘制抗体 CT感染急性病史的女性的反应，确定CT抗原的免疫主导表现， 研究具有阳性CT感染结果的女性之间的差异抗体反应（定义为否 CT在3个月的随访或无抗生素治疗的CT感染的随访或自发分辨率下再感染）和 经历CT重新感染的妇女，并确定这些妇女的功能和保护能力 抗体反应。要测试的中心假设是患者之间的抗体反应会有所不同 比那些经历过CT恢复的CT感染结果阳性的，这些表位 - CT粘附因子的特定抗体将在保护中起重要作用（与CT感染的结合 细胞，中和，抗体介导的嗜中性粒细胞杀伤以及鼠模型中的CT挑战的保护）。 长期目标是通过更好地理解保护性免疫反应来告知疫苗设计， 在有效的CT疫苗中达到高潮。以下特定目标将用于检验假设： 具体目标1：定义女性泌尿生殖器CT感染的天然血清抗体反应。利用深处 序列耦合Biopanning，一种新型技术，使用少量人类血清来细微地绘制 抗体反应在表位级时，我将阐明对CT感染的天然抗体反应。这会 从经验上确定对24 CT抗原的免疫主流表位和B细胞表位。我也会定义 与之相比 那些在抗生素治疗3个月内重新感染CT的人。 具体目标2：研究CT粘附因子表位特异性抗体功能。抗体 将测试患者队列（SA1）之间的免疫主流表位和差异抗体反应 确定针对CT感染的保护能力的功能。使用体外技术，我将确定是否 这些表位特异性抗体可以与CT结合，具有中和能力，并且可以在抗体中起作用 介导的中性粒细胞CT杀死。我还将确定这些抗体是否可以预防A 通过监测CT感染，细菌脱落，CT清除率和上生殖道病理学来监测鼠模型。 该提案将共同研究表位特异性抗体的特异性，功能和作用 防止CT感染的保护，并有可能通过理解来显着推进CT领域 保护性免疫反应并告知未来的疫苗设计。