Project 3: Defining adaptive immune interactions that shape Clostridioides difficile infection

项目 3：定义影响艰难梭菌感染的适应性免疫相互作用

• 批准号: 10625579
• 负责人: Michael C. Abt
• 金额: $ 34.82万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625579
• 关键词: Acute; Age; Animal Model; Animals; Antibodies; Antibody Response; Automobile Driving; B-Lymphocytes; Binding; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Surface Proteins; Cells; Characteristics; Childhood; Chronic Phase; Clinical; Clostridium difficile; Complement; DNA; Data; Defect; Disease; Elderly; Engineering; Feces; Feedback; Filtration; Flow Cytometry; Generations; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Human; Immune; Immune Evasion; Immune Targeting; Immune response; Immune system; Immunity; Immunocompetent; Immunodeficient Mouse; Immunologic Memory; Immunoprecipitation; Impairment; In Situ; In Vitro; Infection; Intestinal Mucosa; Intestines; Large Intestine; Mass Spectrum Analysis; Memory B-Lymphocyte; Messenger RNA; Microscopy; Mucosal Immunity; Mucous body substance; Mus; Natural Immunity; Pathway interactions; Patients; Physiology; Population; Primary Infection; RNA vaccine; Rag1 Mouse; Recurrence; Reporting; Resolution; Risk; Sampling; Serum; Severity of illness; Shapes; Sterility; System; Toxin; Vaccinated; Vaccine Clinical Trial; Vaccine Design; Vaccines; Virulence Factors; Visualization; adaptive immune response; adaptive immunity; age related; aged; draining lymph node; experience; fecal transplantation; high dimensionality; high risk; high risk population; in vivo; metagenomic sequencing; microbial; outcome disparities; pathogen; patient population; pressure; prevent; primary endpoint; recurrent infection; response; success; transcriptome; transcriptome sequencing; transmission process; unvaccinated; vaccine candidate; vaccine development; vaccine response; vaccine trial; vaccine-induced immunity; young adult

SUMMARY: PROJECT 3 - IMMUNOLOGY The quality of the host immune response to Clostridioides difficile infection is one of the strongest predictors of disease severity. Despite the protective capacity of the host immune response, the immune parameters that promote immunity remain poorly understood. Approximately 25-35% of patients that recover from primary C. difficile infection will experience a recurrence episode indicating the host often fails to develop natural immunity following primary infection. Further, multiple vaccine trails have not met primary endpoint of reducing occurrence of infection despite the vaccine candidates eliciting robust antibody responses against C. difficile toxins, the primary virulence factors driving disease. A limited mechanistic understanding of why the natural immune response to infection often does not promote immunity represents a critical roadblock toward the goal of developing a vaccine that will elicit lasting protective immunity in high-risk populations. This project will systematically evaluate the natural immune response to C. difficile infection using both patient sample and a murine infection system. In aim 1 we will compare the capacity of the systemic and intestinal mucosal antibodies elicited following infection to detect and bind to C difficile residing in the intestinal lumen. Successful generation of an antibody response that targets C. difficile in the intestinal tract is dependent on a coordinated C. difficile-specific CD4+ T and B cell response in the intestine and associated draining lymph nodes and is the focus of studies proposed in aim 2. Last, in aim 3 we will investigate the in vivo biogeography and transcriptome of C. difficile in the presence of adaptive immune pressure to identify immune evasion mechanisms employed by C. difficile to promote persistence and transmission. The result of all three aims will feedback into Project 1 (Vaccine Development) to inform mRNA vaccine studies by providing a template how vaccine-induced immunity can be shaped to limit disease, prevent colonization, and recurrence of C. difficile. 1

摘要：项目 3 - 免疫学 宿主对艰难梭菌感染的免疫反应的质量是最强的预测因子之一 疾病的严重程度。尽管宿主免疫反应具有保护能力，但免疫参数 促进免疫力仍然知之甚少。大约 25-35% 的原发性艰难梭菌康复患者。 艰难梭菌感染会出现复发，表明宿主通常无法形成自然免疫力 原发感染后。此外，多项疫苗试验尚未达到减少 尽管候选疫苗引发了针对艰难梭菌的强烈抗体反应，但仍发生了感染 毒素，驱动疾病的主要毒力因素。对原因的有限机械理解 对感染的自然免疫反应通常不会促进免疫力，这是一个关键障碍 实现开发一种疫苗的目标，该疫苗将在高风险人群中引发持久的保护性免疫力 人口。该项目将系统评估对艰难梭菌感染的自然免疫反应 使用患者样本和小鼠感染系统。在目标 1 中，我们将比较系统的能力 感染后引起的肠粘膜抗体可检测并结合存在于肠道中的艰难梭菌 肠腔。成功产生针对肠道中艰难梭菌的抗体反应是 依赖于肠道内协调的艰难梭菌特异性 CD4+ T 和 B 细胞反应以及相关的 引流淋巴结，是目标 2 中提出的研究重点。最后，在目标 3 中，我们将研究 适应性免疫压力存在下艰难梭菌的体内生物地理学和转录组鉴定 艰难梭菌采用免疫逃避机制来促进持久性和传播。结果 所有三个目标都将反馈到项目 1（疫苗开发）中，通过以下方式为 mRNA 疫苗研究提供信息： 提供了如何塑造疫苗诱导的免疫力以限制疾病、预防定植和 艰难梭菌复发。 1