Salmonellosis continues to be a major world-wide health problem. Although Salmonella infections (other than typhoid fever) are usually self limiting, in immunocompromised individuals (e.g. elderly and AIDS patients) non- typhoid Salmonella can cause life threatening disease. S. typhi infections remain a very series problem in third world countries, particularly in children under the age of three. An essential pathogenic feature of all Salmonella spp. is their ability to gain access to mammalian cells that are normally non-phagocytic. The internalization process is the result of an intimate interaction between the bacteria and the host cell which results in the induction of signal transduction pathways that lead to membrane ruffling and bacterial internalization. Another feature of Salmonella infections is that the pathology of this disease is largely due to the host response to the invading pathogen. Little is known about the mechanisms by which Salmonella induces host responses but it is our hypothesis that signal transduction pathways evoked by Salmonella at the host cell surface may lead to the activation of transcription factors with subsequent production of biologically active molecules (e.g. cytokines, eicosenoids). These molecules may in turn modulate both the inflammatory as well as the immune response of the host to these organisms. Recent work from our laboratory has begun to outline the signaling pathways evoked by Salmonella in host mammalian cells. However, mere work is needed to better defined those pathways as well as to understand the Salmonella-induced host cellular mechanisms that lad to the activation of transcription factors. it is an objective of this research project to use a variety of genetic, biochemical and cell biological techniques to define more precisely the host cell signal transduction pathways evoked by Salmonella resulting in bacterial uptake. In addition, we intend to identify nuclear responses evoked by Salmonella that may lead to the activation of transcription factors and subsequent production of modulators of the inflammatory or immune responses. Although we will initially use S. typhimurium in our experiments, the results obtained are likely to be extrapolatable to all Salmonella serotypes and may help to define new concepts around which new drugs can be designed that may help to prevent infections by Salmonella or other intracellular pathogens.
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