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

通过艰难梭菌孢子操纵宿主补体——一种免疫逃避策略。

• 批准号: 9091899
• 负责人: YI XU
• 金额: $ 18.56万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9091899
• 关键词: Adherence; Adopted; Animal Model; Antibiotic Resistance; Antibiotics; Antibody Response; Applications Grants; Attention; Bacillus (bacterium); Bacillus anthracis; Bacillus anthracis spore; Bacillus subtilis; Binding; Binding Proteins; Biological; Cells; Clostridium difficile; Collagen; Complement; Complement Activation; Complement Factor H; Data; Employee Strikes; Epithelial Cells; Epithelium; Funding Mechanisms; Future; Goals; Immune; Immune system; Immunity; Immunosuppression; Infection; Investigation; Knowledge; Lead; Mediating; Membrane Proteins; Methods; Molecular; Names; Nature; Play; Prevalence; Prevention; Procedures; Protein C; Proteins; Recombinant Proteins; Recruitment Activity; Recurrence; Refractory; Relapse; Reporting; Reproduction spores; Severity of illness; Streptococcus pneumoniae; Structure; Surface; Testing; Time; United States; Work; antimicrobial; base; disease transmission; in vitro Assay; in vivo; insight; mortality; mouse model; mutant; novel; novel strategies; pathogen; prevent; public health relevance; resilience

 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.

 描述（由申请方提供）：艰难梭菌感染（CDI）的复发率很高。复发性CDI对抗生素更难治，并与死亡率显著增加相关。研究表明，超过一半的复发性CDI是由于同一菌株的复发，其余的是由于新菌株的再感染。因此，CDI复发引起了人们对两个重要问题的关注：1）C.艰难梭菌在宿主肠道和2）缺乏保护性免疫从以前的CDI发作。这两个问题都没有得到明确的理解，这种缺乏理解的情况阻碍了对复发性CDI的管理和预防。 我们的长期目标是双重的：a）阐明C.艰难的持续定植和缺乏对先前CDI发作的保护，和B）使用获得的知识来开发策略以更好地预防和治疗复发性CDI。由于对抗生素的内在耐药性，宿主C.艰难梭菌孢子是持续感染和疾病传播的关键。 最近的研究表明，在C。艰难梭菌和密切相关的炭疽芽孢杆菌表明，除了其内在的弹性，还有孢子特异性机制，促进殖民。基于我们和其他研究小组的工作，本研究的中心假设是C。艰难梭菌孢子介导与补体调节因子H的结合，并且该结合促进肠道的孢子定殖和复发性CDI。本提案的总体目标是确定具体的C。介导结合T因子H的艰难梭菌表面蛋白，并确定结合的生物学后果。提出了两个具体目标。目的1鉴定C.艰难梭菌孢子使用各种策略。目的2：用体外方法测定结合物的生物学活性 在CDI的小鼠模型中。研究了H因子结合对补体激活、C.将确定艰难梭菌孢子对宿主细胞的粘附、肠道定植、疾病严重程度和抗体应答。C.艰难梭菌孢子不仅由于其固有的弹性而被动地促成复发性CDI，而且还采取特定的机制主动地 促进持续定植和反复感染是新的C. dfficile字段结果 从拟议的工作可能提供了第一次深入了解这一机制，并告知未来的调查，以进一步剖析这一机制的分子细节。进一步的研究可能会导致新的策略，以更好地管理和预防复发的CDI。