Clostridium difficile-host interactions at the intestinal interface

艰难梭菌是一种孢子形成细菌，是腹泻相关性腹泻（CDAD）的主要原因，也是一种有问题的医院获得性病原体。尽管病人是通过摄入孢子而感染的，但只有C。艰难梭菌会产生毒素， CDAD的病理作用，以及C.肠粘膜环境中的艰难梭菌孢子尚未被检查。通过我们先前对霍乱弧菌的研究，我们开发了一种简单、灵活、有效的离体模型，该模型重现了哺乳动物肠道中发现的条件，代表了肠道病原体研究中的一种主要新工具，有望 为开发靶向药物和疫苗铺平道路。该模型将用于确定孢子的萌发速率，以及辅助鉴定诱导萌发的宿主或细菌菌群来源的信号。此外，将使用离体模型来鉴定在细胞凋亡后诱导的基因。 使用基因筛选进行发芽。鉴定影响孢子萌发的信号和了解萌发过程中基因是如何调节的，可能为阻断C.艰难感染 一旦孢子萌发成营养细胞，就不知道它们如何逃避宿主的免疫系统。我们的初步数据表明，在体外生长的细胞，但不是那些生长在肠组织的存在下，可以结合到粘膜抗体，分泌型伊加。C.艰难梭菌，包括是否C。艰难梭菌调节其表面蛋白质的表达以响应宿主环境和对此负责的宿主信号。此外，S-lgA与C.将检查艰难梭菌，包括与S-IgA结合的细胞的命运和C.很难免疫原性细胞表面因子的鉴定和/或免疫逃避机制的理解可能会导致CDAD的新的治疗选择。

Clostridium difficile is a spore-forming bacterium that is the leading cause of antibiotic-associated diarrhea (CDAD) and is a problematic hospital-acquired pathogen. Despite the fact that patients are infected via ingestion of the spores yet only the vegetative form of C. difficile can produce the toxins that result in the pathological effects of CDAD, the molecular basis of germination of C. difficile spores in the intestinal mucosal environment has not been examined. Through our prior work with Vibrio cholerae, we have developed a simple, flexible, and effective ex vivo model that recapitulates the conditions found in the mammalian intestine, representing a major new tool in the study of intestinal pathogens that promises to pave the way for developing virulence-targeted drugs and vaccines. This model will be used to determine the rate of germination of spores as well as aid in the identification of host- or bacterial flora-derived signals that induce germination. In addition, the ex vivo model will be used to identify genes induced upon germination using a genetic screen. Identification of signals that affect spore germination and knowledge of how genes are regulated during germination may provide potential therapeutic targets for blocking C. difficile infection. Once spores have germinated into vegetative cells, it is not known how they evade the host immune system. Our preliminary data indicate that cells grown in vitro, but not those grown in the presence of intestinal tissues, can bind to the mucosal antibody, secretory IgA. The immune evasion strategies employed by C. difficile will be examined, including whether C. difficile modulates the expression of its surface proteins in response to the host environment and what host signal is responsible for this. In addition, the consequences of S-lgA binding to C. difficile will be examined, including the fate of cells bound to S-lgA and possible avoidance strategies used by C. difficile. Identification of immunogenic cell surface factors and/or understanding the mechanisms of immune evasion could lead to novel treatment options for CDAD.