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 In what we believe is an exciting advance, our unpublished experiments have now converged on identification of the sensor as a host protein called Sting (Stimulator of interferon genes).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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Cheng, Mandy I; Chen, Chen; Engström, Patrik et al. (2018) Actin-based motility allows Listeria monocytogenes to avoid autophagy in the macrophage cytosol. Cell Microbiol 20:e12854
Mitchell, Gabriel; Cheng, Mandy I; Chen, Chen et al. (2018) Listeria monocytogenes triggers noncanonical autophagy upon phagocytosis, but avoids subsequent growth-restricting xenophagy. Proc Natl Acad Sci U S A 115:E210-E217
Penn, Bennett H; Netter, Zoe; Johnson, Jeffrey R et al. (2018) An Mtb-Human Protein-Protein Interaction Map Identifies a Switch between Host Antiviral and Antibacterial Responses. Mol Cell 71:637-648.e5
Chen, Chen; Nguyen, Brittney N; Mitchell, Gabriel et al. (2018) The Listeriolysin O PEST-like Sequence Co-opts AP-2-Mediated Endocytosis to Prevent Plasma Membrane Damage during Listeria Infection. Cell Host Microbe 23:786-795.e5
Nguyen, Brittney N; Peterson, Bret N; Portnoy, Daniel A (2018) Listeriolysin O: a phagosome-specific cytolysin revisited. Cell Microbiol :e12988
Price, Jordan V; Jiang, Kallie; Galantowicz, Abigail et al. (2018) Legionella pneumophila Is Directly Sensitive to 2-Deoxyglucose-Phosphate via Its UhpC Transporter but Is Indifferent to Shifts in Host Cell Glycolytic Metabolism. J Bacteriol 200:
Light, Samuel H; Su, Lin; Rivera-Lugo, Rafael et al. (2018) A flavin-based extracellular electron transfer mechanism in diverse Gram-positive bacteria. Nature 562:140-144
Deng, Weiwen; Lira, Victor; Hudson, Thomas E et al. (2018) Recombinant Listeria promotes tumor rejection by CD8+ T cell-dependent remodeling of the tumor microenvironment. Proc Natl Acad Sci U S A 115:8179-8184
Price, April E; Shamardani, Kiarash; Lugo, Kyler A et al. (2018) A Map of Toll-like Receptor Expression in the Intestinal Epithelium Reveals Distinct Spatial, Cell Type-Specific, and Temporal Patterns. Immunity 49:560-575.e6
Majer, Olivia; Liu, Bo; Barton, Gregory M (2017) Nucleic acid-sensing TLRs: trafficking and regulation. Curr Opin Immunol 44:26-33

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