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 各州。这种革兰氏阳性、芽胞形成、严格的厌氧菌最常感染抗生素- 接受治疗的宿主，尽管社区获得性感染正在上升，原因不明。至 艰难梭菌在宿主外生存时会产生休眠的孢子。孢子在代谢上处于休眠状态 能抵抗许多恶劣条件(例如，许多清洗剂、高温、 辐射和抗生素)。在宿主中，艰难梭菌的孢子对胆汁酸做出反应而萌发。 艰难梭菌孢子萌发后，营养细胞产生毒素，触发 宿主的炎症反应，并导致疾病的主要症状。值得注意的是， 艰难梭菌感染的效应物(如毒素受体丰度和炎症)显示 强烈的昼夜节律。这些节律是由分子生物钟产生的 几乎每一个哺乳动物细胞，它们依赖转录反馈环来协调 大约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 艰难梭菌感染、定植和致病。在此探索性应用程序中， 寄主昼夜生物学对艰难梭菌定植能力和寄主生物活性的影响 本课程将探讨艰难梭菌感染的炎症反应。

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.