Faculty Research Page
Howard Hughes Medical Institute Investigator and Professor of Immunology and Molecular MedicineLab 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 new technologies continue to provide exciting advances. Given the continuing global burden of infectious disease, the study of host-pathogen interactions remains 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 the Vance Lab focuses on the following interrelated areas, all of which address the fundamental problem of how pathogens are sensed and eliminated by the innate immune system:
Inflammasomes: guardians of the host cell cytosol. Inflammasomes are multi-protein complexes that assemble in the cytosol of host cells upon detection of various noxious or infectious stimuli. Once assembled, inflammasomes serve as a scaffold for the dimerization and activation of inflammatory caspases, most notably, Caspase-1. Caspase-1 initiates immune resopnses by cleaving and activating key downstream effector proteins. Cells express several different inflammasomes, each of which is responsive to distinct stimuli. We have focused primarily on two inflammasomes: the NAIP–NLRC4 inflammasome that detects bacterial proteins such as flagellin; and the NLRP1 inflammasome that detects pathogen-derived toxins and enzymes. We are particularly interested in how inflammasomes provide resistance against bacterial infections, and also how pathogens evade inflammasome defense. Our studies have focused on two different bacterial pathogens: Legionella pneumophila, the cause of Legionnaires' Disease; and Shigella flexneri, the cause of bacillary dysentery.
Shigella flexneri: new approaches to a globally significant intestinal pathogen. Shigella is a genus of bacteria responsible for severe gastrointestinal infections—shigellosis and dysentery—in humans. It is estimated that there are upwards of 200,000 annual deaths each year due to Shigella, many of which occur in children under the age of five, primarily in developing countries. A major impediment to research on Shigella has been the lack of an in vivo mouse model that faithfully recapitulates the hallmarks of human disease. Our work on inflammasomes has led us to develop the first oral infection mouse model of shigellosis. We are now positioned to answer many fundamental questions about Shigella pathogenesis in vivo, with the aim of exploiting this knowledge in the design of improved vaccines and therapeutics.
Mycobacterium tuberculosis: novel factors controlling lung inflammation. Recently, we have become particularly interested in applying our knowledge of innate immunity to another important globally significant pathogen, Mycobacterium tuberculosis. M. tuberculosis is the causative agent of tuberculosis, and is the single pathogen responsible for more human deaths than any other viral, bacterial or protozoan pathogen. M. tuberculosis was discovered by Robert Koch in 1882, but we remain largely ignorant about fundamental aspects of its microbiology and immunopathogenesis. We are taking advantage of mouse genetic approaches to identify critical host factors that mediate susceptibility and resistance to M. tuberculosis. We discovered how a type I interferon response elicited by M. tuberculosis actually benefits the pathogen. We have also discovered that a novel transcriptional regulator called SP140 is an important mediator of immune resistance to M. tuberculosis. Our work on TB is part of a collaborative program project grant with the Stanley, Cox and Portnoy Labs at Berkeley.
Evolutionary Origins of Innate Immunity. A series of fortuitous observations led us to discover that bacterial molecules called cyclic-di-nucleotides stimulate a specific innate immune response characterized by the production of type I interferons. By using random chemical mutagenesis of mice, we discovered that a host protein called STING is essential for the cytosolic interferon response to cyclic-di-nucleotides. We further showed that STING is a direct cytosolic receptor for cyclic-di-nucleotides. Subsequent work by others showed that cyclic-di-nucleotides are not unique to bacteria but are also produced by a cytosolic DNA sensor protein called cGAS. We then showed that the cyclic-di-nucleotides produced by cGAS have a unique chemical structure that allows them to potently stimulate human STING. We have recently become particularly interested in the evolutionary origins of the STING protein. We were surprised to discover that even sea anemone, organisms that diverged from humans more than 500 million years ago, encode a functional STING protein that binds cyclic-di-nucleotides (pictured above). Sea anemone lack type I interferons, so an important question we are currently pursuing is: what is the evolutionarily ancient function of STING? and is this function conserved in mammalian STING? We recently made the surprising discovery that interferon-independent activities of STING contribute to protection against HSV-1 in vivo.
Host-Pathogen Arms Races and Innate Immune Sensing of Pathogen-encoded Activities. The generally accepted model for how the innate immune system detects pathogens is called the Pattern Recognition model. According to this model, hosts use germline-encoded receptors to bind directly to specific pathogen-encoded molecules, such as lipopolysaccharde or flagellin, that are widely conserved across diverse pathogens and which are not normally found in self cells. Pattern recognition is certainly a major mechanism of pathogen detection, but we have recently been intrigued by alternate mechanisms for pathogen detection. One alternate mechanism, sometimes called Effector-triggered Immunity, proposes that hosts might not only detect pathogen molecules but might also detect the activitiesof pathogen-encoded virulence factors. In the course of our work on the innate immune system, we have uncovered several examples of effector-triggered immunity and determined their underlying molecular mechanism. We believe that it is likely there are more examples to be uncovered and we are currently conducting genetic screens to identify them. Our work has uncovered fascinating examples of host-pathogen arms races in which pathogens deploy virulence factors to evade host immunity, but hosts counteract virulence factors by sensing their activities and initiating secondary responses.
Selected Research Papers
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.
Photo Credit: Mark Hanson of Mark Joseph Studios
Last Updated 2021-08-05