DESCRIPTION (provided by applicant): Campylobacter jejuni is the leading cause of severe bacterial gastroenteritis in the U.S., and has been classified as a food-borne Category B Bioterrorism agent by the NIH. In addition to the tremendous burden of disease due to severe gastroenteritis (>2.4 million cases/yr, in the U.S.), C. jejuni infection is highly associated with the development of Guillain-Barre syndrome, an acute motor paralysis that may result from autoimmune antibodies against C. jejuni antigens. Poultry flocks are ubiquitously and asymptomatically colonized with C. jejuni, and the most probable route of transmission of C. jejuni to humans is probably via consumption of contaminated poultry meat. In its natural habitats, C. jejuni is able to thrive at two different temperatures, 42C (the core temperature of chickens) and 37C (in humans). Consequently, there is likely to be temperature regulation of C. jejuni proteins to facilitate the optimal expression of the subset of proteins appropriate for its current environment (i.e., poultry or humans). Using complementary microarray and proteomics approaches, we have evidence that such temperature regulation occurs. Furthermore, C. jejuni temperature regulation may increase the expression at 37C of proteins that may be important in the course of human disease, and appear to define global regulatory networks that allow the simultaneous regulation of many C. jejuni proteins. We now propose further study of temperature regulation in C. jejuni, focusing on those proteins that are induced at 37C and which may be required for C. jejuni to cause disease in humans. We will achieve these goals using the following 3 specific aims: Specific Aim 1. Using proteomics and microarray, identify and localize C. jejuni proteins that are induced at 37C, and examine interstrain variability in 37C-induced proteins. Specific Aim 2. Characterize the functions and regulation of C. jejuni proteins that are induced at 37C.Specific Aim 3. Elucidate the roles of specific 37C-induced proteins in human epithelial cell binding and invasion in vitro, and in colonization in a mouse model.
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