Bacterial effector subversion of host protein trafficking

描述（由申请人提供）：由肠道细菌引起的腹泻病已被普遍确定为一种重要的地方性健康威胁和食源性疾病的主要来源。在美国，每年有超过7600万例病例和5,000例死亡由食源性疾病引起。肠出血性大肠大肠杆菌（EHEC）尤其重要，因为它是小儿肾衰竭的主要原因，通常通过受污染的肉类和蔬菜产品传播。尽管肠出血性大肠杆菌对人类健康的威胁程度已经得到了充分的认识，但我们仍然不完全了解肠出血性大肠杆菌是如何通过破坏宿主肠道的正常细胞功能而引起腹泻的。 这项研究的中心假设是，NleF通过破坏宿主Tmp 21（p23）蛋白的功能来促进EHEC的毒力，Tmp 21（p23）蛋白是细胞内蛋白转运囊泡的重要组成部分。该项目的具体目标是1）绘制NleF/Tmp 21结合界面，2）表征NleF对宿主蛋白质运输的影响。 这个项目将是重要的，因为它将表征如何肠出血性大肠杆菌毒力因子NleF与宿主蛋白质转运机制的相互作用。预计这些研究将对设计新的战略以对抗肠道病原体产生重大的积极影响。 公共卫生相关性：E.大肠杆菌是食源性疾病的主要来源，因进食未煮熟的牛肉制品或受污染的蔬菜而引致。大肠已经发现大肠杆菌蛋白可能通过改变哺乳动物细胞内蛋白质转运机制的功能而导致结肠炎。申请人正在表征这种蛋白质的生物活性，目的是开发新的E.大肠杆菌和相关的大肠杆菌病原体。

DESCRIPTION (provided by applicant): Diarrheal disease caused by enteric bacteria has been universally established as an important endemic health threat and a major source of food borne disease. Over 76 million cases and 5,000 deaths result from food borne illness in the Unites States annually. Enterohemorrhagic E. coli (EHEC) is especially important because it is the leading cause of pediatric renal failure and is commonly transmitted via contaminated meat and vegetable products. In spite of the appreciated magnitude of the threat to human health caused by EHEC, we still do not fully understand how EHEC causes diarrhea by disrupting the normal cellular functions of the host intestine. The central hypothesis for the proposed research is that NleF contributes to EHEC virulence by subverting the function of the host Tmp21 (p23) protein, an important component of intracellular protein transport vesicles. The specific aims of this project are to 1) map the NleF/Tmp21 binding interface and 2) characterize the influence of NleF on host protein trafficking. This project will be significant because it will characterize how the EHEC virulence factor NleF interacts with the host protein transport machinery. These studies are expected to have a significant positive impact on the design of new strategies to combat diarrheal pathogens. PUBLIC HEALTH RELEVANCE: E. coli is a significant source of food borne disease caused by ingestion of under-cooked beef products or contaminated vegetables. An E. coli protein has been discovered that may contribute to diarrheal disease by altering the function of mammalian intracellular protein transport machinery. The applicant is characterizing the biological activity of this protein with the goal of developing new therapeutic strategies for E. coli and related diarrheal pathogens.