The Interplay Between Host Immunity and Clostridium difficile Pathogenesis

项目总结（见说明）： 艰难梭菌感染（CDI）是发病率和死亡率的重要原因。与CDI相关的疾病范围从无症状定植到轻度结肠炎到严重的假膜性结肠炎。尽管与C.尽管在艰难梭菌感染中，实际上对宿主因素在疾病中的作用机制一无所知。感染个体的某些临床差异可能是由于宿主对C.很难我们假设宿主对C.艰难梭菌是部分负责不同的临床表型中看到的CDI的设置。此外，我们推测，这些可变的反应反映了宿主的遗传差异和可能的表观遗传差异。为了解决这些假设，我们提出了以下具体目标：在第一个目标，我们将描述先天性和适应性免疫反应的C。difficile定植，并确定这种反应在确定疾病表现中的作用。在第二个目标中，我们将鉴定与不同临床结果相关的血清粪便生物标志物和表观遗传变化。本项目将为此目的检查从项目1区获得的样品。第三个目标是研究宿主遗传学/免疫应答与C. difficile基因型在疾病发病机制中的作用。将用C.从项目区域#1的人体研究中生成并表征的艰难梭菌菌株。这将提供一个检查的相对贡献的主机和病原体因素在疾病。 这些实验将加深我们对C. d/Wc/Ve诱导的结肠炎症与无症状定植，并鉴定可用于改善临床治疗和结果的生物标志物。

PROJECT SUMMARY (See instructions): Clostridium difficile infection (CDI) is a significant cause of morbidity and mortality. Disease related to CDI ranges from asymptomatic colonization to mild diarrheal disease to severe pseudomembranous colifis. Despite the extensive characterizafion of the histologic lesions associated with C. difficile infection, virtually nothing is known mechanistically about the contribution of host factors in disease. It is likely that some of the clinical differences encountered in infected individuals are due to variafion in host response to colonization with C. difficile. We hypothesize that variation in the host innate and adaptive responses for C. difficile are in part responsible for the different clinical phenotypes that are seen in the setting of CDI. Furthermore, we speculate that these variable responses reflect underiying genetic and possibly epigenetic differences in the host. To address these hypotheses we propose the following specific aims: In the first aim we will characterize the innate and adaptive immune response to C. difficile colonization and determine the role of this response in determining the disease manifestations. In the second aim we will identify serum fecal biomarkers and epigenetic changes that correlate distinct clinical outcomes. This aim will examine samples obtained from the Project area #1 for this purpose. The third aim will examine the interaction between host genetics/immune response and C. difficile genotype in the pathogenesis of disease. Mice with defined differences in host response will be challenged with C. difficile strains generated and characterized from the human studies in Project area #1. This will provide an examinafion ofthe relative contribution of host and pathogen factors in disease. These experiments will increase our understanding ofthe host and microbial mechanisms of C. d/Wc/Ve-induced colonic inflammation vs. asymptomatic colonization and identify biomarkers that can be used to improve clinical treatments and outcomes.