Jenifer Coburn, PhD
Medicine (Division of Infectious Disease), and Center for Infectious Disease Research
Medical College of Wisconsin
Research Focus: Spirochete Pathogenesis and Host Cell Responses
PhD: Tufts University (1991) Molecular Microbiology
My laboratory studies the interactions with mammalian cells of Borrelia burgdorferi, the agent of Lyme disease, and Leptospira interrogans, an agent of leptospirosis. Both are spirochetes that can establish persistent infection in immunocompetent reservoir animals, and are significant causes of morbidity and mortality in humans. While leptospirosis is uncommon in the continental US, it is a significant illness in agricultural and urban slum areas in the developing world, particularly where water sources are contaminated by animal urine. Lyme disease, in contrast, is the most common vector-borne illness in the Northern hemisphere.
B. burgdorferi binds to members of a family of receptors on the surface of human cells termed "integrins", which are important in many cellular processes, including inflammation and blood vessel growth. Using a phage display library of B. burgdorferi genomic DNA, we identified a B. burgdorferi protein that mediates bacterial binding to β3-chain integrins, and have defined portions of this protein that participate in integrin recognition. Our current work focuses on determining the role of Borrelia-integrin recognition in the course of infection and the development of Lyme disease in the mouse model. We have also studied the mammalian cell response to B. burgdorferi strains that do or do not express the β3-chain integrin ligand, and by microarray analyses, have identified several signaling/regulatory pathways that show integrin-ligand specific changes in expression. Some of these may be important to the ability of this organism to disseminate from the site of the tick bite to other tissues. We also discovered that another B. burgdorferi protein, BBB07, signals through integrin α3β1 to promote a proinflammatory response in human chondrocytes, which may contribute to the pathogenesis of Lyme arthritis. Our phage display library was also used in vivo to identify B. burgdorferi proteins that bind to vessel walls in specific tissues such as the joint and heart, and further characterization of these proteins is underway.
The goals of the work with Leptospira are to identify mammalian cell surface receptors for these bacteria, and to determine the mammalian cell responses to pathogenic vs. saprophytic Leptospira strains. We have found that pathogenic leptospires bind more efficiently to the cell surface than to the extracellular matrix, and that some of this attachment is mediated by proteoglycans on the mammalian cell. We are currently investigating the nature of additional host receptors, and building a phage display library of Leptospira interrogans DNA to facilitate identification of bacterial proteins that mediate attachment to host cells. Some of the host responses to L. interrogans are reminiscent of those to B. burgdorferi, e.g. those that may facilitate dissemination of the organisms, while other pathways are clearly distinct.
Our ultimate goal is to employ the recent dramatic advances in spirochete genetics to identify new strategies to prevent or treat infection and disease, to identify bacterial and mammalian molecules that contribute to infection and the resulting disease, and to better understand the biology of the organisms in their natural infection cycles.
Room: TBRC C3980