Project Number: 1235-52000-055-00
Project Type: Appropriated

Start Date: Mar 28, 2004
End Date: Mar 15, 2009

Objective:
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.

Approach:
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. This research includes BSL-2 level work recertified by SOHES on 6/12/08.