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（由申请人提供）：艰难梭菌感染（CDI）的复发率很高。复发性 CDI 对抗生素更难治疗，并且与死亡率显着增加相关。研究表明，超过一半的复发性 CDI 是由于同一菌株复发，其余的则是由于新菌株再次感染。因此，CDI 复发引起人们对两个重要问题的关注； 1) 艰难梭菌在宿主肠道中持续定植，2) 缺乏先前 CDI 发作的保护性免疫力。这些问题都没有被清楚地理解，并且缺乏理解阻碍了 CDI 复发的管理和预防。 我们的长期目标有两个： a) 阐明艰难梭菌持续定植和缺乏针对先前 CDI 发作的保护的分子机制，b) 利用所获得的知识制定策略以更好地预防和治疗复发性 CDI。由于对抗生素和宿主抗菌药物的内在耐药性，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杆菌的研究证据表明，除了其内在的恢复能力之外，还有促进定植的孢子特异性机制。基于我们和其他小组的工作，该提案的中心假设是艰难梭菌孢子的表面蛋白介导与补体调节因子 H 的结合，并且这种结合促进孢子在肠道定植和复发性 CDI。本提案的总体目标是鉴定介导 H 因子结合的特定艰难梭菌表面蛋白，并确定结合的生物学后果。提出了两个具体目标。目标 1 将使用多种策略鉴定艰难梭菌孢子上的特定 H 因子结合蛋白。目标 2 将利用体外测定结合的生物活性 测定和 CDI 小鼠模型。将确定 H 因子结合对补体激活、艰难梭菌孢子与宿主细胞的粘附、肠道定植、疾病严重程度和抗体反应的影响。艰难梭菌孢子不仅由于其内在的弹性而被动地导致复发性 CDI，而且还采用特定的机制主动地促进 CDI 的概念。 促进持续定植和反复感染在艰难梭菌领域是新颖的。结果 拟议的工作可能会首次提供对该机制的见解，并为未来的研究提供信息，以进一步剖析该机制的分子细节。进一步的研究可能会带来更好地管理和预防 CDI 复发的新策略。