Nutritional immunity and microbial competition during Clostridioides difficile infection

艰难梭菌感染期间的营养免疫和微生物竞争

• 批准号: 10538799
• 负责人: Eric P Skaar
• 金额: $ 47.05万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-13 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538799
• 关键词: Affect; Antibiotic Therapy; Antibiotics; Bacteroides; Binding; Binding Proteins; Biological Markers; Cells; Chelating Agents; Clinical; Clostridium difficile; Complex; Data; Development; Dietary Zinc; Disease; Event; Gastrointestinal tract structure; Gene Expression; Genes; Genetically Modified Animals; Growth; Human; Immune; Immune system; Immunologic Factors; Incidence; Individual; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Iron; Knowledge; Lead; Leukocyte L1 Antigen Complex; Manganese; Mediating; Metal exposure; Metals; Microbe; Modeling; Molecular; Mus; Names; Nutrient; Nutritional; Nutritional Immunity; Outcome; Pathogenesis; Pattern; Physiology; Play; Predisposition; Prevention strategy; Process; Production; Property; Proteins; Public Health; Recurrence; Reproduction spores; Research; Role; Severities; Shapes; Site; Starvation; System; Testing; Toxin; Trace metal; Up-Regulation; Vertebrates; Virulent; Zinc; base; cell type; chelation; chemokine; cofactor; colonization resistance; cost; cytokine; defined contribution; dietary; dietary excess; enteric infection; enteric pathogen; experimental study; gastrointestinal epithelium; gene product; gut colonization; gut microbiota; host-microbe interactions; human microbiota; immunoregulation; member; microbial; microbial community; microbiome; microbiota; neutrophil; normal microbiota; nutrient deprivation; pathogen; prevent; recruit; response; therapeutic development; therapeutically effective; transcriptional reprogramming; treatment strategy; young adult

SUMMARY Clostridioides difficile (formerly named Clostridium difficile) is a Gram-positive, spore-forming pathogen, and the leading cause of nosocomial and antibiotic-associated intestinal infections. Susceptibility to C. difficile infection (CDI) often follows antibiotic treatment and subsequent disruption of the resident intestinal microbiota, however the rise of infections in healthy young adults suggests that there are additional factors that contribute to CDI. To colonize the gastrointestinal tract, C. difficile must compete with both the host and members of the gut microbiota for critical nutrients. Access to nutrient metals can profoundly impact the outcome of CDI as metals are required cofactors for approximately 30% of all proteins. This fact is exploited by host metal binding proteins which sequester nutrient metals to restrict microbial growth in a process termed nutritional immunity. A hallmark of CDI is the secretion of potent toxins that cause severe damage to the gastrointestinal epithelium and trigger the production of pro-inflammatory cytokines and chemokines. These events initiate the immune-mediated recruitment of inflammatory factors to the site of infection. One of the most abundant inflammatory proteins that accumulates at the site of CDI is calprotectin. Calprotectin is the most abundant protein in neutrophils and is a component of nutritional immunity that directly inhibits microbial growth through nutrient metal sequestration. Calprotectin is also a potent immunomodulatory protein, and a common clinical inflammatory biomarker whose abundance correlates with CDI severity. It is unknown how the massive infiltration of calprotectin affects metal availability in the gastrointestinal tract and shapes competition between C. difficile and members of the gut microbiota. In addition, how C. difficile adapts to calprotectin-dependent metal limitation and resists nutritional immunity during CDI remains unclear. We propose a model whereby nutrient metals make a critical contribution to the outcome of CDI. Toxin driven inflammation drives the recruitment of immune cells into the gut which leads to the accumulation of large amounts of CP. CP chelates available nutrient metals and exerts potent pro- inflammatory activities. This massive inflammatory response and redistribution of nutrients alters C. difficile gene expression and affects the interaction between C. difficile and members of the microbiota. Finally, we hypothesize that C. difficile encodes multiple gene products that compete with both CP and the microbiota for nutrient metals and this competition has a profound effect on the outcome of CDI. Experiments described in this proposal will test this model and define the contribution of nutritional immunity to the pathogenesis of C. difficile, determine the role of metal binding and immune cell recruitment in the protective properties of calprotectin, and identify C. difficile genes required to compete with the microbiome for nutrient metals during inflammation. Collectively, the findings from this proposal will inform the development of effective therapeutic or prevention strategies for the treatment of CDI.

概括 梭状芽胞杆菌艰难梭菌（以前命名为艰难梭菌）是一种革兰氏阳性，形成孢子的病原体，并且是 医院和抗生素相关肠道感染的主要原因。艰难梭菌感染的敏感性 （CDI）经常遵循抗生素治疗并随后破坏居民肠道菌群，但是 健康的年轻人感染的兴起表明，还有其他导致CDI的因素。到 殖民地胃肠道，艰难梭菌必须与宿主和肠道菌群的成员竞争 用于关键营养素。由于需要金属，因此获得营养金属可以深刻影响CDI的结果 大约30％的所有蛋白质的辅助因子。这一事实是由宿主金属结合蛋白利用的 隔离营养金属以限制称为营养免疫的过程中的微生物生长。 CDI的标志 是有效毒素的分泌 促炎性细胞因子和趋化因子的产生。这些事件启动免疫介导的 招募炎症因素到感染部位。最丰富的炎症蛋白之一 在CDI的位置积聚是钙粘蛋白。钙卫蛋白是中性粒细胞中最丰富的蛋白质，是一种 营养免疫的成分，可以直接通过营养金属螯合而直接抑制微生物的生长。 钙卫蛋白也是一种有效的免疫调节蛋白，也是一种常见的临床炎症生物标志物 丰度与CDI严重程度相关。尚不清楚钙骨蛋白的大规模浸润如何影响金属 胃肠道的可用性，并塑造艰难梭菌与肠道成员之间的竞争 微生物群。另外，艰难梭菌如何适应钙染色素依赖性金属限制并抵抗营养 CDI期间的免疫力尚不清楚。我们提出了一个模型，营养金属做出关键的贡献 CDI的结果。毒素驱动的炎症将免疫细胞募集到肠道中 大量CP的积累。 CP螯合物可用的营养金属，并发挥有效的利润 炎症活动。这种巨大的炎症反应和养分的重新分布改变了艰难梭菌基因 表达并影响艰难梭菌与菌群成员之间的相互作用。最后，我们 假设艰难梭菌编码与CP和Microbiota竞争的多个基因产品 营养金属和该竞争对CDI的结果产生了深远的影响。在此描述的实验 建议将测试该模型，并定义营养免疫对艰难梭菌发病机理的贡献， 确定金属结合和免疫细胞募集在钙染色素的保护特性中的作用，以及 确定与微生物组竞争炎症期间营养金属所需的艰难梭菌基因。 总的来说，该提案的发现将为有效的治疗或预防的发展提供信息 治疗CDI的策略。