Intracellular pathogens and innate immunity

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Program Director/Principallnvestigator (Last, (Last, First, Middle): Portnoy, Daniel2 P01 AI063302-06 Program Director/Principal InVestigator First, Middle): Portnoy, Daniel A. A. 2 P01 A1063302-06 ABSTRACT renewal P01 This application was submitted as a competitive renewal of a P01 originally submitted in response to a submitted in response to a Program Announcement (PA) from N PAIDas part of the Biodefense and Emerging Infectious Disease Disease Announcement (PA) from NIAID as part of the Biodefense and Research Program. The proposed research is focused on the interaction of five diverse facultative Research Program. The proposed research is focused on the interaction of five diverse facultative intracellular microbial pathogens with macrophages, a central problem of infectious disease research, with a central problem of infectious disease research, with important ramifications for global health, biodefense and emerging infections. The proposed research relies important ramifications for global health, biodefense and emerging infections. The proposed research relies heavily on the use of bacterial and host mutants to examine a macrophage cytosolic surveillance pathway of heavily on the use bacterial and host mutants to examine a macrophage cytosolic surveillance pathway of innate immunity that detects intracellular pathogens. A central hypothesis of this P01 is that microbial innate immunity that detects pathogens. A central hypothesis of this P01 is that microbial molecules, secreted or released through auxiliary secretion systems, are specifically recognized by host secreted released through auxiliary secretion systems, are specifically recognized by host receptors leads to the activation of IRF3 cytosolic receptors. Stimulation of these receptors leads to the activation of 1RF3 and the subsequent receptors. expression of IFNb and co-regulated genes. This model provides a possible mechanism by which host cells expression lFNb and co-regulated genes. This model provides a possible mechanism by which host cells are able to detect microbial products secreted by live, replicating microorganisms. The Specific Aims are: I. secreted by live, replicating microorganisms. The Specific Aims are: I. Identify and characterize molecular determinants that contribute to stimulating the host cytosolic pathways of Identify and characterize determinants that contribute to stimulating the host cytosolic pathways of innate immune recognition by examining macrophage transcriptional responses to Mycobacterium innate immune recognition by examining macrophage transcriptional responses to Mycobacterium tuberculosis, Histoplasma capsulatum, Francise/la tularensis, and Listeria monocytogenes. Identification of tuberculosis, Histoplasma capsulatum, Francisella tularensis, and Listeria monocytogenes. Identification of these determinants will be accomplished using forward genetic screens and a bioassay that detects IFN-b, a forward and bioassay IFN-b, a cytokine specific to the cytosolic pathway. II. Identify host pathways and bacterial ligand(s) that activate the cytokine specific to the cytosolic pathway. II . Identify host pathways and bacterialligand(s) that activate the cytosolic response. II I. Characterize the role(s) of the cytosolic pathways of innate immune recognition in role(s) cytosolic Ill. pathways immune recognition in animal models of infection. Aims II and III will be supported by Core C (animal core). IV. Establish common animal models infection. Aims II and Ill by (animal core). IV. Establish common and unique host transcription profiles that establish signature responses to microbial pathogens. Utilize responses to microbial pathogens. Utilize transcriptional signatures to identify common and distinct pathways and mechanisms of host response. Aim common and pathways and mechanisms host response. Aim IV will be supported by Core B (transcriptional profiling core). Although this proposal does not directly IV will be supported by Core B (transcriptional profiling core). Although this proposal does not directly it does involve BSL2 and BSL3 pathogens and accordingly, each PI involve select agents, it does involve BSL2 and BSL3 pathogens and accordingly, each P1 has described their commitment to ensure biosafety. The aims represent a reduction in scope from the original grant biosafety. The aims represent a reduction in scope from the original grant submission in order to focus on critical experiments that can be accomplished in two years. Please see the submission focus on critical experiments that can be accomplished in two years. Please see the Revised