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

摘要：项目3-免疫学 宿主对艰难梭状芽胞杆菌感染的免疫反应质量是预测 疾病的严重性。尽管宿主免疫反应具有保护能力，但免疫参数 促进免疫力仍然鲜为人知。大约25%-35%的患者从原发性C。 艰难梭菌感染会反复发作，表明宿主经常无法形成自然免疫力。 在初次感染之后。此外，多项疫苗试验还没有达到减少 尽管候选疫苗对艰难梭菌产生了强大的抗体反应，但仍发生了感染 毒素是导致疾病的主要毒力因素。有限的机械论理解为什么 对感染的自然免疫反应往往不能促进免疫是一个关键的障碍 朝着开发一种疫苗的目标迈进，这种疫苗将在高危人群中诱导持久的保护性免疫 人口。该项目将系统地评估艰难梭菌感染的自然免疫反应。 同时使用患者样本和小鼠感染系统。在目标1中，我们将比较系统的容量 和感染后激发的肠道粘膜抗体，以检测和结合驻留在 肠腔。成功地产生针对肠道中艰难梭菌的抗体反应是 依赖于艰难梭菌在肠道中的协调特异性CD4+T和B细胞反应 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 艰难梭菌在适应性免疫压力下的活体生物地理学和转录组分析 艰难梭菌利用免疫逃避机制促进持久性和传播性。其结果是 所有三个AIMS都将反馈给项目1(疫苗开发)，以通过以下方式为mRNA疫苗研究提供信息 提供了一个模板，说明如何塑造疫苗诱导的免疫以限制疾病、防止殖民和 艰难梭菌复发。 1

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