Bacterial effector subversion of host protein trafficking

描述（申请人提供）：由肠道细菌引起的腹泻病已被普遍认为是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7600万病例和5000人死于食源性疾病。肠出血性大肠杆菌（EHEC）尤其重要，因为它是儿童肾衰竭的主要原因，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得到充分认识，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导致腹泻的。

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.