Role of circadian rhythms in the susceptibility to Clostridium difficile infection

项目摘要 艰难梭菌现在是美国医院获得性感染的最常见原因。 States.这种革兰氏阳性、孢子形成、严格厌氧菌最常感染抗生素- 接受治疗的宿主，但社区获得性感染正在上升，原因不明。到 在宿主外存活，C.艰难梭菌产生休眠孢子。孢子处于新陈代谢休眠状态 对许多苛刻条件具有抗性的细菌形式（例如，许多清洁剂，热， 辐射和抗生素）。在寄主中，C.艰难梭菌孢子响应胆汁酸而萌发。 继C.艰难孢子萌发时，营养细胞产生毒素， 宿主的炎症反应和引起疾病的主要症状。值得注意的是， C.艰难梭菌感染（例如，毒素受体丰度和炎症）表现出 强烈的昼夜节律。这些节奏是由分子生物钟产生的， 几乎每一个哺乳动物细胞，并依赖于转录反馈回路协调 约10-15%的基因组的节律性表达。宿主的昼夜节律 生理学表明，正常的宿主昼夜节律可能会影响效率， 其中C。艰难梭菌感染、定殖并引起疾病。在这个探索性的应用程序中， 寄主昼夜生物学对C.很难在宿主体内定植 对C.将探索艰难梭菌感染。

Project Summary Clostridium difficile is now the most common cause of hospital-acquired infections in the United States. This Gram-positive, spore-forming, strict anaerobe most commonly infects antibiotic- treated hosts, though community-acquired infections are on the rise for unknown reasons. To survive outside a host, C. difficile produces dormant spores. Spores are metabolically dormant forms of bacteria that are resistant to many harsh conditions (e.g., many cleaning agents, heat, radiation and antibiotics). In a host, C. difficile spores germinate in response to bile acids. Following C. difficile spore germination, the vegetative cells produce the toxins that trigger the host’s inflammatory response and that cause the primary symptoms of disease. Remarkably, the effectors of C. difficile infection (e.g., toxin receptor abundance and inflammation) exhibit strong circadian rhythms. These rhythms are generated by molecular circadian clocks found in virtually every mammalian cell, and which rely on transcriptional feedback loops to coordinate the rhythmic expression of about 10-15% of the genome. The circadian nature of the host physiology suggests that the normal host circadian rhythms may impact the efficiency with which C. difficile infects, colonizes and causes disease. In this exploratory application, the effects of host circadian biology on the ability of C. difficile to colonize and on the host’s inflammatory response to C. difficile infection will be explored.