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

总结：项目3 -免疫学 宿主对艰难梭菌感染的免疫应答的质量是艰难梭菌感染的最强预测因子之一。 疾病严重程度。尽管宿主免疫应答具有保护能力，但 促进免疫力仍然知之甚少。大约25-35%的患者从原发性C。 艰难梭菌感染将经历复发发作，表明宿主通常不能产生天然免疫力 原发感染后。此外，多个疫苗试验尚未达到降低 尽管候选疫苗引起针对C.艰难 毒素是导致疾病的主要毒力因子。一个有限的机械理解为什么 对感染的自然免疫反应通常不能促进免疫，这是一个关键的障碍 我们的目标是开发一种疫苗，在高危人群中引起持久的保护性免疫。 人口。本项目将系统地评价对C.菌感染 使用患者样本和鼠感染系统。在目标1中，我们将比较系统的容量 以及感染后引发的肠粘膜抗体，以检测并结合存在于肠粘膜中的艰难梭菌。 肠腔成功产生靶向C的抗体应答。肠道中的艰难梭菌是 依赖于一个协调的C.肠内艰难梭菌特异性CD 4 + T和B细胞应答及相关 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 C.在适应性免疫压力的存在下， 免疫逃避机制采用C.难以促进持久性和传播。的结果 所有这三个目标将反馈到项目1（疫苗开发）中，为mRNA疫苗研究提供信息， 提供了一个模板，疫苗诱导的免疫力可以如何形成，以限制疾病，防止殖民化， C.复发很难 1