Faculty Research Page
Howard Hughes Investigator and 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?
Current work in my lab focuses on the following interrelated areas, all of which address the fundamental problem of how bacterial pathogens are sensed and eliminated by the innate immune system:
Innate immunity to Legionella pneumophila. 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. We are interested in understanding how host cells detect the presence of Legionella. Our hypothesis is that disruptions of host cell physiology by Legionella induce host innate immune responses. For example, Legionella blocks host protein synthesis. We have found that this block is detected by host cells and, in response, host cells initiate production of pro-inflammatory cytokines that protect against infection. We are interested in determining the molecular mechanism of this response and its importance during bacterial infection. We are also investigating how the innate immune response is able to successfully eliminate Legionella infection.
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 and other Naip family members in immune responses and resistance to Legionella and other pathogens. We also generating novel genetically engineered models to assess the role of Naips and flagellin-sensing in autoimmune pathology.
Detection of the anthrax protease toxin by the Nlrp1 inflammasome. Nlrp1 is another innate immune sensor protein that is a relative of the Naip proteins described above. Nlrp1 also forms inflammasomes, but we have found that its mechanism of activation is distinct from that of the Naips. In particular, we have found that direct proteolysis of Nlrp1 by the anthrax protease toxin is sufficient to activate formation of the Nlrp1 inflammasome. We are interested in determining the biochemical mechanism for this response. In addition, activation of Nlrp1 and Naips both lead to a form of host cell death called pyroptosis. We are interested in understanding the mechanisms of how inflammasomes induce pyroptotic cell death, and the role of pyroptosis during infection and inflammation in vivo.
The cGAS-STING pathway and detection of bacterial cyclic-di-nucleotides and DNA. Another innate immune pathway that has caught our interest is a cytosolic immunosurveillance pathway that senses pathogen-derived nucleic acids. One class of unusual nucleic acids are cyclic-di-nucleotides. These molecules include c-di-AMP and c-di-GMP that are produced by bacteria where they regulate various aspects of host physiology. Since c-di-AMP and c-di-GMP are not made by mammalian hosts, they represent suitable targets for innate immune recognition. Indeed, in collaboration with the Portnoy Lab on campus, 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. In particular, we are interested in a mammalian enzyme called cGAS that produces endogenous cyclic-di-nucleotides in response to the cytosolic presence of foreign DNA. In collaboration with the Hammond Lab at Berkeley, we showed that the cyclic-di-nucleotide produced by cGAS contains an unusual 2'-5' phosphodiester bond. We were able to show that this small chemical difference produces a significantly enhanced ability to activate the STING pathway in human cells. In collaboration with the Doudna Lab on campus, we continue to be interested in the mechanism by which cyclic-di-nucleotides activate STING.
Tuberculosis. A nascent area of interest for the lab is the intracellular bacterial pathogen Mycobacterium tuberculosis (MTb). MTb currently infects about a third of the world's population, and causes approximately 1 million deaths per year. We lack an effective vaccine for this pathogen, and antibiotic therapies are increasingly problematic due to rising rates of multi-drug resistant infections. The innate immune response to MTb remains poorly understood. In collaboration with the Stanley and Cox labs on campus, we are undertaking a variety of approaches, including novel forward genetic screens, to try to better understand this important bacterial pathogen.
Selected Research Papers
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.
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.
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
von Moltke J, Ayres JS, Kofoed EM, Chavarría-Smith J, Vance RE (2013) Recognition of bacteria by inflammasomes. Annual Review of Immunology 31:73-106.
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.
Photo Credit: Mark Hanson of Mark Joseph Studios
Last Updated 2015-08-27