Faculty Research Page

Russell E. Vance

Russell Vance

Howard Hughes Medical Institute Investigator and Professor of Immunology and Pathogenesis

Lab Homepage: http://mcb.berkeley.edu/labs/vance/

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Research Interests

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 new technologies continue to provide exciting advances. 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

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 and how this influences the outcome of infections in vivo.

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. 

Detection of the bacterial toxins 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 discovered that STING is an evolutionarily ancient protein and that a functional homolog is even found in Nematostella vectensis, a sea anemone >500 million years diverged from humans. By studying Nematostella, we are interested in discovering the evolutionarily ancient function of 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 more than a 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 to better understand the remarkable success of this pathogen.

Selected Publications

Selected Research Papers

Sandstrom A, Mitchell PS, Goers L, Mu EW, Lesser CF, Vance RE (2018) Functional degradation: a mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes. https://www.biorxiv.org/content/early/2018/05/09/317834
Nichols RD, von Moltke J, Vance RE (2017) NAIP/NLRC4 inflammasome activation in MRP8(+) cells is sufficient to cause systemic inflammatory disease. Nat Commun. 20;8(1):2209.
Rauch I, Deets KA, Ji DX, von Moltke J, Tenthorey JL, Lee AY, Philip NH, Ayres JS, Brodsky IE, Gronert K, Vance RE (2017) NAIP-NLRC4 Inflammasomes Coordinate Intestinal Epithelial Cell Expulsion with Eicosanoid and IL-18 Release via Activation of Caspase-1 and -8. Immunity 46(4):649-659
De Leon JA, Qiu J, Nicolai CJ, Counihan JL, Barry KC, Xu L, Lawrence RE, Castellano BM, Zoncu R, Nomura DK, Luo ZQ, Vance RE (2017) Positive and Negative Regulation of the Master Metabolic Regulator mTORC1 by Two Families of Legionella pneumophila Effectors. Cell Reports 21(8):2031-2038
Tenthorey JL, Haloupek N, López-Blanco JR, Grob P, Adamson E, Hartenian E, Lind NA, Bourgeois NM, Chacón P, Nogales E, Vance RE (2017) The structural basis of flagellin detection of NAIP5: a strategy to limit pathogen immune evasion. Science, 358(6365):888-893.
Barry KC, Ingolia NT, Vance RE (2017) Global analysis of gene expression reveals mRNA superinduction is required for the inducible immune response to a bacterial  pathogen. Elife. Apr 6;6. pii: e22707
Chavarría-Smith J, Mitchell PS, Ho AM, Daugherty MD, Vance RE (2016) Functional and  Evolutionary Analyses Identify Proteolysis as a General Mechanism for NLRP1 Inflammasome Activation. PLoS Pathog. Dec 7;12(12):e1006052
Kranzusch PJ, Wilson SC, Lee AS, Berger JM, Doudna JA, Vance RE (2015) Ancient Origin of cGAS-STING Reveals Mechanism of Universal 2',3' cGAMP Signaling. Molecular Cell Sep 17;59(6):891-903.
Tenthorey JL, Kofoed EM, Daugherty MD, Malik HS, Vance RE (2014) Molecular basis for specific recognition of bacterial ligands by NAIP/NLRC4 inflammasomes. Molecular Cell Apr 10;54(1):17-29.
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.

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.

Selected Reviews

Jones JD, Vance RE, Dangl JL (2016) Intracellular innate immune surveillance devices in plants and animals. Science 354(6316)
Vance RE, Eichberg MJ, Portnoy DA, Raulet DH (2017) Listening to each other: Infectious disease and cancer immunology. Sci Immunol. 2(7)
Margolis SR, Wilson SC, Vance RE. Evolutionary Origins of cGAS-STING Signaling. Trends Immunol. 38(10):733-743. PMID: 28416447
Price JV, Vance RE (2014) The macrophage paradox. Immunity Nov 20;41(5):685-93. 

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 2018-07-27