Grant: Operating Grant

Since pathogens proliferate rapidly (often doubling in minutes), the immune system must operate swiftly in order to combat the increasing pathogen burden. Some of the specialized immune cells such as macrophages and dendritic cells handle the pathogens rapidly and solicit the help of other immune cells (T cells) to control the pathogen burden comprehensively. However, some pathogens, such as Salmonella Typhimurium (ST), which induces a typhoid-like disease in mice and gasteroenteritis in humans, appear to escape this early recognition by the immune system. This results in rapid fatality in susceptible hosts and establishment of a chronic disease in resistant hosts. Outbreaks of such food- and water-borne pathogens are on the rise, and there are no efficient vaccines. In this proposal we will unravel the fundamental mechanisms that are lacking during infection of the immune cells with ST. We will modify the pathogen so that T cells are engaged early on and evaluate whether this modification makes the pathogen vulnerable to immune attack. Our results indicate that ST induces rapid death of macrophages and this seems to be initiated by the key anti-viral cytokine, interferon (IFN)-I. Thus, what protects us against viral infections seems to promote susceptibility against other pathogens. How the expression of IFN-I upon ST infection leads to rapid death of macrophages, the quintessential immune cell is one of the key questions we will be unraveling. These studies will lead to the identification of strategies that can be exploited for development of therapeutics.