2007 Annual Report 1a.Objectives (from AD-416) 1)Develop mouse models of orally-acquired enteric viral and food-borne bacterial infections to assess the effect of nutritionally-induced oxidative stress on the pathogenesis of enteric infections. 2)Determine the effect of dietary-induced oxidative stress on the pathogenesis of enteric viral and bacterial infections of the GI tract. 3)Determine the parameters of innate and acquired mucosal immunity, and GI function that are altered by oxidative stress. 4)Map the redistribution of trace elements important for GI and immune function, and resistance to oxidative stress that are altered by diet and enteric infections. 5)Determine the mechanism(s) by which oxidative stress alters intestinal physiology and immunity to intestinal pathogens by a) examining changes in the redox state that affect specific signal transduction and gene activation pathways related to GI and immune function, and b) assessing whether selection of mutated strains of virus or bacteria with altered pathogenicity occurs under conditions of oxidative stress. 1b.Approach (from AD-416) The research proposal is based on the hypothesis that nutritionally-induced oxidative stress will increase the pathogenecity of viral and bacterial infections of the gastrointestinal (GI) tract by altering mucosal immunity, the gut physiological response to infection, and/or by selecting for pathogenic strains better adapted to growth under conditions of oxidative stress. Two mouse models will be developed to examine the effect of oxidative stress on GI tract infections. The models will use reovirus and Salmonella spp. as organisms that represent two major food-borne pathogen groups, viruses and bacteria, respectively. Indices of both innate and acquired immunity will be examined including induction of cytokines, chemokines, and nitric oxide production, and macrophage, B- and T-cell function. The effects of nutrition, infection, and oxidative stress on GI functions including absorption, secretion, and motility will be assessed. The effect of nutrition and oxidative stress on the cellular redox status and activation of transcription factors will be evaluated as potential mechanisms that lead to altered pathogenicity and gut function. The effect of oxidative stress on pathogen growth and evolution also will be evaluated. The intestinal barrier is the first line of defense against orally acquired infections and is the conduit through which all nutrients pass. Food can be a major source of antioxidants and therefore diets poor or enriched in antioxidants could have a major impact on the outcome of viral and bacterial infections. 3.Progress Report The lead scientist presented a seminar on current studies of selenium and vitamin E deficiencies that affect mucosal immune responses during bacterial and parasitic infection at the Orville Levander Symposium at the Annual Experimental Biology Meeting in Washington, DC. in May, 2007. 4.Accomplishments Food-borne Pathogen Model Demonstrates that Dietary Induced Oxidative Stress Increases Pathology: Citrobacter rodentium infection in a mouse model mimics many of the pathologies associated with E. coli infections in humans. Mice fed a diet deficient in selenium and vitamin E had enhanced pathology and delayed clearance of C. rodentium that appear to be related to a delayed immune response to infection demonstrated by decreased cytokine production. The results indicate that reduced antioxidants in the diet contribute to greater disease intensity and systemic infections from food-borne bacteria. Conducted as part of the National Program 107 Component 6, Relationship between Diet, Genetics, Lifestyle, and the Prevention of Obesity and Disease. Diets Containing Fish Oil Positively Impact the Colonic Response to Bacterial Infection: Serendipitous testing of the Citrobacter rodentium infection model in mice showed that fish oil added as a diet to control for the effect of antioxidant status on severity of infection resulted in reduced tissue pathology. Further examination of this observation should provide a basis for testing the impact of dietary fish oils on prevention of disease and reduced bacterial infection after exposure to food-borne bacteria. Conducted as part of the National Program 107 for Human Nutrition Component 6, Relationship between Diet, Genetics, Lifestyle, and the Prevention of Obesity and Disease. 5.Significant Activities that Support Special Target Populations None 6.Technology Transfer Number of non-peer reviewed presentations and proceedings 7 Review Publications Scanlan, B.J., Tuft, B., Elfrey, J.E., Smith, A., Zhao, A., Morimoto, M., Chmielinska, J.J., Tejero-Taldo, M.I., Mak, I.T., Weglicki, W.B., and Shea-Donohue, T. 2007. Intestinal inflammation caused by magnesium deficiency alters basal and oxidative stress-induced intestinal function. Molecular and Cellular Biochemistry. Jul27;[Epub ahead of print].