Epithelium, dendritic cells, and Clostridium difficile associated colitis

描述（由申请方提供）：艰难梭菌是伪膜性结肠炎的病原体，占腹泻相关性腹泻病例的四分之一。随着近年来超强毒株的出现，C.在北美和欧洲，艰难梭菌感染（CDI）显著增加，导致住院时间长、发病率和死亡率高。CDI被认为主要是由外毒素TcdA和TcdB介导的，其使Rho家族的低分子量GTdB葡糖基化，导致大量液体分泌、急性炎症和结肠粘膜坏死。我们的长期目标是了解C.艰难梭菌感染，并利用这些知识设计更好的免疫干预措施，以减少CDI的发病率和疾病的严重程度。肠上皮细胞（IEC）与肠抗原呈递细胞（APC）（如树突状细胞（DC）和巨噬细胞）在肠道中的相互作用协调粘膜免疫稳态和炎症反应。我们的目的是阐明IEC和肠道DC在暴露于C.艰难梭菌毒素，并确定其相互作用的性质，引发肠道炎症和组织破坏。为了实现这一目标，我们将测试几个工作假设：1）C。艰难梭菌毒素中毒的IEC能够动员和激活DC; 2）在严重的CDI病例中，C.艰难梭菌毒素可以穿过严重受损的肠屏障并进一步激活DC和巨噬细胞;和3）促炎细胞因子TNF-α与毒素协同作用以诱导IEC的凋亡，从而加剧组织破坏和小肠结肠炎。通过验证这些假设，我们不仅希望更好地了解C。艰难梭菌毒素诱导严重的小肠结肠炎，而且IEC-DC相互作用在一般肠道炎性疾病的发生和发展中的作用。我们相信，这样的理解将有助于我们设计更好的免疫干预措施来对抗CDI和其他肠道炎症性疾病。

DESCRIPTION (provided by applicant): Clostridium difficile, an etiologic agent for pseudomembranous colitis, accounts for a quarter cases of antibiotic-associated diarrhea. With the recent emergence of hypervirulent strains, the incidence of C. difficile infection (CDI) has increased significantly in both North America and Europe, causing lengthy hospitalization, substantial morbidity and mortality. CDI is thought to be mainly mediated by exotoxins TcdA and TcdB, which glucosylate low molecular mass GTPase of the Rho family, leading to massive fluid secretion, acute inflammation, and necrosis of the colonic mucosa. Our long-term goal is to understand the mechanisms mediating intestinal inflammation in C. difficile infection and to utilize this knowledge for the design of better immune interventions in order to reduce the incidence of CDI and severity of the disease. The interaction of intestinal epithelial cells (IECs) with intestinal antigen presenting cells (APCs), such as dendritic cells (DCs) and macrophages, in the gut orchestrates mucosal immune homeostasis and inflammatory response. Our objective is to elucidate the immune response of IECs and intestinal DCs after their exposure to C. difficile toxins and to determine the nature of their interaction on initiating intestinal inflammation and tissue destruction. To achieve this objective, we will test several working hypotheses: 1) C. difficile toxin-intoxicated IECs are capable of mobilizing and activating DCs; 2) In severe cases of CDI, C. difficile toxins can cross a severely damaged intestinal barrier and further activate DCs and macrophages; and 3) proinflammatory cytokine TNF-a synergizes with the toxins to induce apoptosis of IECs, thus exacerbating tissue destruction and enterocolitis. By testing these hypotheses, we expect to gain a better understanding of not only the underlying mechanisms by which C. difficile toxins induce severe enterocolitis, but also the role of IEC-DC interaction in the onset and development of intestinal inflammatory diseases in general. We believe that such an understanding will help us to design better immune interventions against CDI and other intestinal inflammatory diseases.