Enterotoxigenic Escherichia coli, or ETEC, is an important cause of bacterial diarrheal illness. Infection with ETEC is the leading cause of travelers' diar rhea and a major cause of diarrheal disease in underdeveloped nations, especially among children. These pathogens, as well as other enteric bacteria that use contact-dependent secretion systems, represent important threats to food safety, biosecurity, and animal health. In many cases, vaccines are not available or are ineffective, and the basic molecular microbiology of the host-pathogen interaction is relatively poorly understood. Additionally, the bacterial virulence proteins utilize molecular mechanisms that are also conserved among viruses of importance to biosecurity. We have discovered several novel molecular mechanisms by which bacterial proteins subvert the host innate immune system to promote bacterial colonization and transmission. We are employing our unique knowledge of these proteins and their mammalian targets to studies of metabolic syndromes and cancer. We are also developing novel proteomic techniques to identify vaccine targets in other organisms. The overall objective of this application is to identify and characterize these newly discovered ETEC-host signaling pathways involved in regulating pathogen colonization and diarrheal disease. This will be accomplished by testing the following central hypothesis: LT promotes ETEC adherence, and thus colonization of the small intestine, by activating signaling pathways that remodel the intoxicated cell for adherence and activate the expression of bacterial adhesins.