Investigation of the molecular basis of Salmonella Typhimurium Intestinal persistence

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The bacterium Salmonella accounts for about 125 million incidents of disease worldwide each year, and nearly a million deaths. The morbidity and mortality caused by this pathogen has a significant impact on the economies of both resource rich and resource poor countries. Most cases of non-typhoidal Salmonella result from fecal contamination of food and food products. A common and therefore critical step for this is the entry of the bacterium into the food chain from livestock and poultry, the common zoonotic reservoir for this pathogen.While a large body of literature describes the mechanisms by which Salmonella establishes infection in the intestine, comparatively little is known about how Salmonella persists. Decreasing the amount of Salmonella in animals at slaughter is important to controlling Salmonella food-borne disease because it is the primary risk factor for introduction of this pathogen into the food chain destined for human consumption. Salmonella uses distinct mechanisms for initial colonisation and persistent colonisation and the latter represent novel targets for approaches to decrease the amount of Salmonella in livestock when they arrive at slaughter. However, in order to develop new approaches it is essential to first identify how Salmonella remains associated with the intestine in the face of competition from good bacteria resident in the intestine and the response by the host animal aimed at clearance of bacterial pathogens. This programme of work will identify all the genes encoded by Salmonella that are involved in the ability of this pathogen to remain in the intestine of livestock for prolonged periods. The relative importance of newly discovered persistence factors in this study and the previously described persistence factors ShdA and MisL will be determined in order to inform the optimal strategy for the design of intervention to decrease Salmonella colonisation. ShdA and MisL are found on the surface of Salmonella where they are known to interact with host proteins but exactly how this contributes to prolonged colonisation of the intestine is not known. We will determine how ShdA and MisL contribute to intestinal persistence, extending on a large body of published work. We will use a combination of an in vivo model of intestinal persistence developed by the applicant, studies on animal cells grown in the lab to determine the impact of ShdA and MisL on interaction of Salmonella with the host, and investigate how these bacterial proteins interact with proteins of the host. The outcome of this study will be a comprehensive overview of the intestinal persistence factors encoded by Salmonella and an understanding of the molecular basis of intestinal persistence mediated by ShdA and MisL. This data analyses will complement efforts by the livestock industry to devise strategies to decrease the incidence of Salmonella carriage that include farm-yard practice and the potential implementation of a vaccine against Salmonella.