Faculty and Research
Faculty by Name
Russell Vance
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Russell Vance
Assistant Professor of Immunology and Pathogenesis
Lab Homepage: http://mcb.berkeley.edu/labs/vance/
Research Interests
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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?
Current Projects
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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 Naip5 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. The mechanism by which Naip5 protects host macrophages is still largely mysterious, but our recent studies indicate that Naip5 regulates activation of caspase-1. We have generated and are characterizing Naip5 knockouts to determine its function in immune responses and resistance to Legionella and other pathogens.
Cytosolic detection of bacterial flagellin by macrophages. It is well established that mammalian cells can detect the presence of microbes by recognizing the presence of microbially-derived molecules such as lipopolysaccharide. We have recently shown that macrophages appear to respond to the cytosolic presence of bacterial flagellin, the primary structural component of flagella. We have further shown that recognition of flagellin is essential for initiation of macrophage resistance to Legionella. We are seeking to extend these studies to establish the general importance of flagellin-detection and its molecular basis.
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 flagellin-sensing Naip5/Ipaf pathway. Interestingly, the various pathways for sensing L. pneumophila seem to be non-redundant with each other in providing immune defense. We are interested in characterizing these pathways to understand better what microbial features are sensed and how they lead to protective immune 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 Publications
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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 .
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, online August 3
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
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.
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-.
Last Updated 2009-08-14