Manipulation of host complement by Clostridium difficile spores - an immune evasion strategy.

 描述(申请人提供)：艰难梭菌感染(CDI)复发率高。复发的CDI对抗生素更耐药，并与显著增加的死亡率相关。研究表明，超过一半的复发性CDI是由于对同一菌株的复发，其余的是由于再次感染新的菌株。因此，CDI的复发引起了人们对两个重要问题的关注：1)艰难梭菌在宿主肠道中的持续定植；2)对以前的CDI发作缺乏保护性免疫。这两个问题都没有得到清楚的了解，这种缺乏了解的情况阻碍了对复发性CDI的管理和预防。我们的长期目标有两个：a)阐明艰难梭菌持续定植和缺乏保护的分子机制(S)，以及b)利用所获得的知识制定策略，更好地预防和治疗复发的CDI。由于对抗生素和宿主抗菌剂的内在耐药性，艰难梭菌孢子是持续感染和疾病传播的关键。 最近对艰难梭菌和密切相关的炭疽芽孢杆菌的研究表明，除了它们固有的弹性外，还有促进定植的孢子特有的机制。基于我们和其他团队的工作，本建议的中心假设是艰难梭菌孢子表面蛋白介导与补体调节因子H的结合，并且该结合促进肠道孢子定植和复发CDI。这项建议的总体目标是鉴定介导t因子H结合的艰难梭菌表面蛋白(S)，并确定结合的生物学后果。提出了两个具体目标。目的1利用多种策略鉴定艰难梭菌孢子上的H因子结合蛋白。目标2将在体外测定结合的生物活性 在CDI的小鼠模型中进行检测。H因子结合对补体激活、艰难梭菌孢子与宿主细胞的黏附、肠道定植、疾病严重程度和抗体反应的影响将被确定。艰难梭菌孢子不仅由于其内在的弹性而被动地促进复发的CDI，而且还采用一种特定的机制积极地 促进持续定植和反复感染在假丝酵母菌领域是新的。结果 从拟议的工作中可能首次提供对这一机制的见解，并为未来的研究提供信息，以进一步剖析这一机制的分子细节。进一步的研究可能导致更好地管理和预防CDI复发的新策略。

 DESCRIPTION (provided by applicant): Clostridium difficile infections (CDI) have a high rate of recurrence. Recurrent CDI are more refractory to antibiotics and are associated with significantly increased mortality. Studies suggest that over half of the recurrent CDI are due to relapse with the same strain and the remainder due to reinfection with a new strain. CDI recurrence therefore draws attention to two important issues; 1) persistent colonization of C. difficile in the host gut and 2) the lack of protective immunity from previous episodes of CDI. Neither of these issues is clearly understood and this lack of understanding hinders the management and prevention of recurrent CDI. Our long-term goals are two-fold; a) to elucidate the molecular mechanism(s) underlying C. difficile persistent colonization and the lack of protection from previous episodes of CDI, and b) to use the knowledge gained to develop strategies to better prevent and treat recurrent CDI. Due to intrinsic resistance to antibiotics an host antimicrobials, C. difficile spores are key to persistent infections and disease transmission. Recent evidence from studies in C. difficile and closely related Bacillus anthracis suggests that in addition to their intrinsic resilience, there are spore-specific mechanisms that promote colonization. Based on work by us and other groups, the central hypothesis in this proposal is that surface proteins of C. difficile spores mediate binding to complement regulator factor H and that the binding promotes spore colonization of the gut and recurrent CDI. The overall objective in this proposal is to identify the specific C. difficile surface protein(s) that mediate binding t factor H and to determine the biological consequences of the binding. Two specific aims are proposed. Aim 1 will identify the specific factor H binding protein on C. difficile spores using a variety of strategies. Aim 2 will determine the biological activities of the binding using in vitro assays and in a mouse model of CDI. The effect of factor H binding on complement activation, adherence of C. difficile spores to host cells, gut colonization, disease severity and antibody responses will be determined. The concept that C. difficile spores not only passively contribute to recurrent CDI due to their intrinsic resilience, but also adopt a specific mechanism to actively promote persistent colonization and recurrent infections is novel in the C. dfficile field. Results from the proposed work may provide for the first time insights into this mechanism and inform future investigations to further dissect the molecular details of this mechanism. Further studies may lead to novel strategies to better manage and prevent recurrent CDI.