Intracellular pathogens remain a major cause of global mortality and morbidity. By evasion of extracellular defenses, such as antibodies, intracellular pathogens pose a unique challenge to the immune systems of their hosts. A fundamental question we address is how intracellular pathogens are sensed by the innate immune system. In the past few years, we and others have discovered that intracellular pathogens trigger a variety of different cytosolic immunosurveillance pathways. These pathways appear to play important roles in shaping protective innate and adaptive responses. However, the molecular basis of cytosolic immunosurveillance remains poorly characterized, and it is likely that additional pathways remain to be discovered. Our studies are motivated by our belief that a better understanding of innate immunity is central to the improved design of new vaccines, adjuvants and immunotherapeutics. Exciting recent work from our group and others has shown that unique bacterial nucleotides, cyclic-di-GMP and cyclic-di-AMP, are novel and potent stimulator of innate and adaptive immune responses. The field now confronts a major outstanding question: what is the host sensor that specifically detects cyclic-di-nucleotides? We are taking genetic and biochemical approaches to address this fundamental question. In what we believe is an exciting advance, our unpublished experiments have now converged on identification of the sensor as a host protein called Sting (Stimulator of interferon genes). We identified a novel Sting mutant mouse in a forward genetic screen using ENU mutagenesis in mice. Using this mutant, we found Sting is essential for responses to c-dinucleotides. In addition, we have recently found that radiolabelled c-di-GMP binds specifically to Sting. Thus, our Specific Aims are: (1) Determine how the interaction of Sting with cyclic-di-nucleotides leads to an IFN response (2) Distinguish the role of Sting in the cytosolic response to cyclic-di-nucleotides from the role of Sting in the cytosolic response to DNA, and distinguish these functions of Sting in the response to three intracellular bacterial pathogens (L. monocytogenes, M. tuberculosis, and L. pneumophila) (3) Identify novel regulators of innate immunity to three intracellular bacterial pathogens (L. monocytogenes, M. tuberculosis, and L. pneumophila) by continuing to perform forward genetic screens in mice.

Public Health Relevance

Infectious diseases remain a major cause of global mortality and morbidity. The design of novel immunotherapeutics, adjuvants and vaccines is predicated on a better understanding of how the innate immune system detects pathogens and initiates protective responses. Our proposal aims to fulfill this goal by dissection of the molecular mechanisms by which intracellular bacterial pathogens (and the unique bacterial nucleic acids they produce) are sensed by the immune system.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-QV-I)
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University of California Berkeley
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Kranzusch, Philip J; Lee, Amy S Y; Wilson, Stephen C et al. (2014) Structure-guided reprogramming of human cGAS dinucleotide linkage specificity. Cell 158:1011-21
Burke, Thomas P; Loukitcheva, Anastasia; Zemansky, Jason et al. (2014) Listeria monocytogenes is resistant to lysozyme through the regulation, not the acquisition, of cell wall-modifying enzymes. J Bacteriol 196:3756-67
B├ęcavin, Christophe; Bouchier, Christiane; Lechat, Pierre et al. (2014) Comparison of widely used Listeria monocytogenes strains EGD, 10403S, and EGD-e highlights genomic variations underlying differences in pathogenicity. MBio 5:e00969-14
Tenthorey, Jeannette L; Kofoed, Eric M; Daugherty, Matthew D et al. (2014) Molecular basis for specific recognition of bacterial ligands by NAIP/NLRC4 inflammasomes. Mol Cell 54:17-29
Lee, Bettina L; Barton, Gregory M (2014) Trafficking of endosomal Toll-like receptors. Trends Cell Biol 24:360-9
Sivick, Kelsey E; Arpaia, Nicholas; Reiner, Gabrielle L et al. (2014) Toll-like receptor-deficient mice reveal how innate immune signaling influences Salmonella virulence strategies. Cell Host Microbe 15:203-13
Archer, Kristina A; Durack, Juliana; Portnoy, Daniel A (2014) STING-dependent type I IFN production inhibits cell-mediated immunity to Listeria monocytogenes. PLoS Pathog 10:e1003861
Arpaia, Nicholas; Barton, Gregory M (2013) The impact of Toll-like receptors on bacterial virulence strategies. Curr Opin Microbiol 16:17-22
Isaac, Dervla T; Coady, Alison; Van Prooyen, Nancy et al. (2013) The 3-hydroxy-methylglutaryl coenzyme A lyase HCL1 is required for macrophage colonization by human fungal pathogen Histoplasma capsulatum. Infect Immun 81:411-20
Aachoui, Youssef; Leaf, Irina A; Hagar, Jon A et al. (2013) Caspase-11 protects against bacteria that escape the vacuole. Science 339:975-8

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