Grant: Operating Grant

To circumvent the rapid proliferation of intracellular bacteria, the immune system must operate rapidly. Cells of the innate and acquired immune system are endowed with different roles in order to control the pathogen comprehensively during early- and late-stages. However, some evasive pathogens, such as Salmonella Typhimurium (ST), which induces a typhoid-like disease in mice and gasteroenteritis in humans, are highly virulent and cause a chronic and sometimes fatal infection. Outbreaks of such food- and water-borne pathogens are on the rise, and they are often the reason for co-morbidity in other chronic inflammatory diseases. Vaccines available are not highly efficacious. In this proposal we will unravel the role of a critical molecule called FoxO3a. This molecule is normally present in the nucleus of cells where it modulates the expression of genes that play role in cell survival, cell proliferation and inflammation. Our preliminary data indicates that FoxO3a plays a critical role in promoting survival of hosts during a chronic infection with Salmonella Typhimurium, as hosts die rapidly in the absence of FoxO3a. We will use various cell biological, immunological and biochemical techniques to unravel the mechanisms that allow FoxO3a to promote survival of hosts during a chronic infection. These studies will lead to the identification of strategies that can be exploited for development of therapeutics against chronic inflammatory diseases.