Associate Professor of Immunology and PathogenesisLab Homepage: http://mcb.berkeley.edu/labs/vance/
How do mammals defend themselves against the diverse world of microbial pathogens? This is a fundamental question that has intrigued biologists for over a century, yet some of the most important advances in our understanding have occurred only in the past decade. Given the continuing global burden of infectious disease, the study of host-pathogen interactions continues to be a pressing area of investigation.
My lab is interested in all aspects of the complex interrelationship between pathogens and their hosts. In particular, we apply the modern tools of biology and genetics to answer a variety of questions at a molecular level: how is the presence of pathogenic bacteria sensed by hosts? Are pathogenic bacteria distinguished from harmless bacteria, and if so, how? What innate immune mechanisms protect cells from pathogens? How do cells coordinate defenses that are appropriate for various categories of pathogens? What mechanisms have pathogens evolved to evade host defenses?
Many of our studies focus on a gram-negative bacterium, Legionella pneumophila, the causative agent of a severe pneumonia called Legionnaires' Disease. Legionella has evolved a variety of sophisticated mechanisms for manipulating host cells, and is representative of a class of bacterial pathogens that grow intracellularly within specialized vacuoles that evade fusion with lysosomes. Legionella is also experimentally accessible, as it grows readily in vitro and can be genetically manipulated at will.
Role of the Naip 'inflammasomes' in immune defense against intracellular bacteria. Classical genetic studies have demonstrated that a host protein, Naip5, is essential for resistance to Legionella. Naip5 is a member of a large class of 'pathogen-detector' proteins that are believed to coordinate host immune responses upon recognition of pathogen-derived molecules. Our studies have demonstrated that Naip5 is a cytosolic detector of flagellin. Interestingly, we were also able to show that a related protein, called Naip2, functions to detect a different protein derived from the secretion systems of pathogenic bacteria. Once activated, both Naip2 and Naip5 assemble into large multi protein complexes, called the inflammasomes, that initiates potent inflammatory responses by activation of a downstream protease called caspase-1. In general the mechanisms of inflammasome activation remain poorly understood and are a major focus for the lab. We have generated and are characterizing Naip5 knockouts to determine the in vivo function of Naip5 in immune responses and resistance to Legionella and other pathogens.
Novel cytosolic surveillance pathways for sensing infection. We have recently uncovered evidence for several new cytosolic pathways that sense bacterial infection. These pathways are distinct from the Naip pathway. We are interested in characterizing these pathways to understand better what microbial features are sensed and how they lead to protective immune responses. One pathway that has particularly caught our interest is a cytosolic immunosurveillance pathway that senses bacterial-derived nucleic acids called cyclic dinucleotides. Cyclic dinucleotides include c-di-AMP and c-di-GMP and are unique signaling molecules that regulate various aspects of bacterial physiology. Since c-di-AMP and c-di-GMP are not made by mammalian hosts, they represent suitable targets for innate immune recognition. Indeed, we recently showed that the host protein Sting functions as a direct mammalian sensor of cyclic dinucleotides. We are continuing to investigate the mechanism by which Sting senses nucleic acids and initiates protective host responses.
Genetic screens. Only very few host genes required for the resistance to Legionella and other intracellular pathogens have been identified. We are commencing longer-term projects using ENU mutagenesis to identify novel host genes essential for resistance to various intracellular pathogens. We are also taking advantage of the genetic accessibility of Legionella to identify bacterial genes important for pathogenesis.
Selected Research Papers
von Moltke J, Trinidad NJ, Moayeri M, Kintzer AF, Wang SB, van Rooijen N, Brown CR, Krantz BA, Leppla SH, Gronert K, Vance RE (2012) Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature 490(7418):107-11.
Ayres JS, Trinidad NJ, Vance RE (2012) Lethal inflammasome activation by a multidrug resistant pathobiont upon antibiotic disruption of the microbiota. Nature Medicine 18(5):799-806.
Kofoed EM, Vance RE (2011) Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477(7366):592-5.
Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B, Hyodo M, Hayakawa Y, Vance RE (2011) STING is a direct innate immune sensor of cyclic-di-GMP. Nature 478(7370):515-8.
Sauer JD, Sotelo-Troha K, von Moltke J, Monroe KM, Rae CS, Brubaker SW, Hyodo M, Hayakawa Y, Woodward JJ, Portnoy DA, Vance RE (2011) The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides. Infection & Immunity 79(2):688-94.
Fontana MF, Banga S, Barry KC, Shen X, Tan Y, Luo ZQ, Vance RE (2011) Secreted bacterial effectors that inhibit host protein synthesis are critical for induction of the innate immune response to virulent Legionella pneumophila. PLoS Pathogens 7(2):e1001289.
Monroe KM, McWhirter SM, Vance RE (2009) Identification of host cytosolic sensors and bacterial factors regulating the type I interferon response to Legionella pneumophila. PLoS Pathogens Nov;5(11).
McWhirter SM, Barbalat R, Monroe KM, Fontana MF, Hyodo M, Joncker NT, Ishii KJ, Akira S, Colonna M, Chen ZJ, Fitzgerald KA, Hayakawa Y, Vance RE (2009) A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP. Journal of Experimental Medicine 206(9):1899-911.
Lightfield KL*, Persson J*, Brubaker SW, Witte CE, von Moltke J, Dunipace EA, Henry T, Sun YH, Cado D, Dietrich WF, Monack DM, Tsolis RM, Vance RE (2008) Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin. Nature Immunology 9:1171-8. *=contributed equally
Ren T, Zamboni DS, Roy CR, Dietrich WF, Vance RE (2006) Flagellin-deficient Legionella mutants evade caspase-1 and Naip5-mediated macrophage immunity. PLoS Pathogens 2:e18-.
Burdette DL, Vance RE (2013) STING and the innate immune response to nucleic acids in the cytosol. Nature Immunology 14(1):19-26. doi: 10.1038/ni.2491von Moltke J, Ayres JS, Kofoed EM, Chavarría-Smith J, Vance RE (2013) Recognition of bacteria by inflammasomes. Annual Review of Immunology 31:73-106.
Fontana MF & Vance RE (2011) Two signal models in innate immunity. Immunological Reviews Sep;243(1):26-39. doi: 10.1111/j.1600-065X.2011.01037.x.
Vance RE, Isberg RR, Portnoy DA (2009) Patterns of pathogenesis: discrimination of pathogenic and nonpathogenic microbes by the innate immune system. Cell Host & Microbe 6:10-21.
Persson J,Vance RE (2007) Genetics-squared: combining host and pathogen genetics in the analysis of innate immunity and bacterial virulence. Immunogenetics 59: 761-778.
Last Updated 2013-04-25