A central problem in microbial pathogenesis is how cells of the immune system recognize and respond to pathogens, and conversely, how pathogens avoid and/or manipulate the host response. In order to approach this problem, we have chosen to focus on the interaction between the intracellular bacterial pathogen, Listeria monocytogenes and the immune cells, macrophages. Macrophages, express surface and cytosolic innate immune receptors that recognize conserved molecules of microbial origin, leading to induction of host inflammatory responses. Ironically, while macrophages are important effector cells of the immune system, they are permissive hosts for intracellular pathogens, and it is still not clear how they sense and respond to live intracellular pathogens. This research proposal aims to directly identify mechanisms by which intracellular pathogens activate the innate immune system. We recently performed a forward genetic screen for L. monocytogenes mutants that induce an enhanced or diminished host innate immune response. Using this unbiased approach we identified L. monocytogenes multi-drug resistance (MDR) transporters that controlled the magnitude of a host cytosolic surveillance pathway, leading to the production of Type I interferon response. In this research program we wish to continue with this approach and (I). Identify additional L. monocytogenes molecular determinants that involved in activation of host innate immune pathways. (II). Using genetic and biochemical approaches we will study the regulation and function of the newly identified L. monocytogenes MDRs in vivo and their role in activation of the Type I interferon response. (III). Identify bacterial ligands that activate the Type I interferon response. We hypothesize that bacterial ligands are transported by the MDRs to the host cytosol where they are recognized. We will use bacterial mutants over-expressing MDRs to identify the MDR-specific substrate(s).
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