Research Interests:
Host-pathogen interactions - Pathogenic and commensal microbes have evolved to co-exist with their mammalian hosts and host defense strategies. Thus, research on the molecular aspects of microbe-host interactions has historically elucidated basic concepts in genetics, cell biology, immunology, and other areas of biology and biochemistry. In addition, these studies often have immediate relevance to human disease.
Our lab uses interdisciplinary approaches to study host-pathogen interactions. We manipulate both the pathogen and the host, and are particularly interested in (1) defining how microbes activate or subvert host immune responses, and (2) determining how these processes contribute to, or protect against, infectious and inflammatory disease.
We primarily use Listeria monocytogenes as a model pathogen in our studies. L. monocytogenes is a Gram-positive bacterium that can infect and replicate within the cytosol of practically any animal cell. The image at the right shows macrophages infected with L. monocytogenes. The bacterium has a fascinating life cycle within the host cell: It secretes a variety of virulence proteins the break open phagosomes, promote bacterial nutrient acquisition and growth in the host cell cytosol. Other secreted bacterial proteins co-opt the host cell’s actin cytoskeleton, and enable the bacterium to spread from one cell to another (without ever leaving the intracellular environment). The ability of intracellular pathogens to undergo cell-to-cell spread was first described for Listeria and Shigella, but has since been observed in other pathogenic microbes as well - including vaccinia virus and Mycobacteria species.
L. monocytogenes also shares genetic and physiological similarities with other deadly Gram-positive bacterial pathogens like Bacillus anthracis, Streptococci, Staphylococci, and Mycobacteria. Thus, results from our studies using L. monocytogenes may help to understandfundamental features of other infectious and inflammatory diseases.
I. The role of virulence proteins secreted by the SecA2 pathway in bacterial virulence and immune subversion. We recently identified a new secretion system, called SecA2, which is found in L. monocytogenes and other important Gram-positive bacterial pathogens. SecA2 is required for L. monocytogenes virulence and secretes a subset of bacterical proteins that also contribute to virulence. We hypothesize that a subset of these proteins modulates intracellular signaling pathways in macrophages and possibly other infected cells. The presumed pathway for proteins secreted by SecA2 is shown here. We have shown that a subset of proteins are preferentially secreted by SecA2, and at least some of these are important for the bacterium’s ability to cause disease. We believe that certain of these proteins interfere with detection of bacterial infection by the innate immune system. Our current experiments seek to further define the effects of these secreted proteins on the host’s response to infection.
II. The basis and consequences of the natural killer (NK) cell response to bacterial infection. NK cells are innate lymphocytes that respond to inflammatory cytokines, stress signals, and infection. Although they do not produce antigen specific receptors like T or B cells, these cells can recognize infected cells and products released from infected cells. Such recognition activates the NK cell, and can lead to the lysis of infected cells and the production of cytokines and other factors that regulate innate immunity and set the stage for development of adaptive immune responses. NK cells protect the host against some tumors and viruses, but their precise roles in immunity to these agents and to bacterial infections, are not clear. We are investigating how L. monocytogenes activates NK cells and how NK cell activation influences other immune responses and thus the outcome of host-pathogen interactions.
Key Publications:
