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（由适用提供）：艰难梭菌感染（CDI）的复发率很高。复发性CDI对抗生素更难治性，并且与死亡率显着增加有关。研究表明，超过一半的复发性CDI是由于相同的应变复发而引起的，其余部分是由于新菌株的重新感染而引起的。因此，CDI复发引起人们对两个重要问题的关注。 1）在宿主肠道中艰难梭菌的持续定殖和2）缺乏对以前的CDI发作的受保护的免疫力。这些问题都没有清楚地理解，缺乏理解阻碍了经常性CDI的管理和预防。我们的长期目标是两个方面。 a）阐明艰难梭菌持续定殖的基本机制，以及缺乏对以前的CDI发作的保护，b）使用所获得的知识来制定策略以更好地预防和治疗复发性CDI。由于对抗生素的固有耐药性宿主抗菌素，艰难梭菌孢子是持续感染和疾病传播的关键。 来自艰难梭菌和密切相关的炭疽杆菌的研究的最新证据表明，除了它们的内在弹性外，还有散射特异性的机制可以促进定殖。基于我们和其他群体的工作，该提议中的中心假设是艰难梭菌孢子的表面蛋白中位数结合与补体调节因子H的中间结合，并且结合促进了肠道和复发性CDI的分散定植。该建议的总体目标是确定中位结合因子H并确定结合的生物学后果的特定特异性艰难梭菌表面蛋白。提出了两个具体目标。 AIM 1将使用各种策略在艰难梭菌孢子上确定特定因子H结合蛋白。 AIM 2将使用体外确定结合的生物学活性 测定和在CDI的小鼠模型中。因子H结合对完成激活，艰难梭菌对宿主细胞的粘附，肠道定植，疾病严重程度和抗体反应的影响。艰难梭菌孢子不仅因其内在的弹性而被动地促进了CDI的概念，而且还采用了一种特定的机制来积极地 促进持续的定殖和复发感染在C. dfficile领域是新颖的。结果 从拟议的工作中可以提供对该机制的首次见解，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。进一步的研究可能导致新的策略更好地管理和预防复发CDI。