Host Cell Signaling Pathways Induced by Salmonella

PROJECT SUMMARY Salmonellosis continues to be a major Public Health challenge resulting in more than 300,000 death world- wide. In the US alone, Salmonella causes an estimated 1 million infections resulting in annual economic burden of $2.8 billion. Salmonella enterica encompasses multiple serovars that are associated with distinct pathogenic features and host specificities. Some serovars (e. g. S. Typhimurium) exhibit broad host specificity, cause self-limiting gastroenteritis, and are one of the most common causes of food-borne illnesses in the industrialized world. In contrast, other serovars such as S. Typhi exhibit remarkable host specificity limiting their ecology to the human host where it causes typhoid fever, a systemic disease that leads to an estimated 200,000 deaths worldwide. The pathogenicity of all S. enterica serovars requires the activity of two type III protein secretion systems (T3SS) encoded within their pathogenicity islands 1 and 2. These T3SSs direct the translocation of a battery of bacterial effectors with the capacity to modulate a variety of cellular functions. Working in conjunction with one another, these effectors modulate actin cytoskeleton dynamics, host-cell gene expression, vesicle trafficking, and innate and acquired immune responses, thus allowing Salmonella to gain access to and replicate within host cells, avoid host defenses, induce intestinal inflammation, and reach deeper tissues. Despite the significant progress, however, much remains to be learned as the biochemical activities and/or relevant cellular targets of many Salmonella effectors remain uncharacterized. The objective of this proposed research is to study host/Salmonella interactions that are shaped by the coordinated activities of its T3SS effectors. We will focus our efforts on the study of mechanisms by which an intrinsic host defense pathway controls Salmonella replication within cells, and how the bacteria counter this defense mechanism with its effector proteins. In addition, we will examine how some of this effector proteins trigger intestinal inflammation, which is critical for Salmonella pathogenesis. These studies will advance the understanding of the cell biology of Salmonella enterica infections and potentially facilitate the development of novel therapeutic and prevention strategies. Furthermore, these studies may establish new paradigms of host-pathogen interactions that may be applicable to other important pathogens that have evolved close associations with their respective hosts.