Medicine (Infectious Diseases)
Microbiology and Immunology
Medical College of Wisconsin
Director, Center for Infectious Disease Research
Research Focus: Bacterial Pathogenesis
Tufts University (1991) Molecular Microbiology
Our research interests focus on pathogenic spirochetes, a group of bacteria that are able to cause persistent, disseminated infections in immunocompetent animals, including humans. We are currently working with Borrelia burgdorferi, which is maintained in a tick-animal cycle in nature. We also work with another pathogenic spirochete, Leptospira interrogans. Leptospires are maintained in infected animals in nature, but can also survive in water and mud. The focus of our work with both Borrelia and Leptospira is to identify and then test the biologic significance of bacterial proteins that help the bacteria bind to mammalian cell surface receptors, to identify the mammalian cell surface receptors recognized by the bacteria, and ultimately the biological and pathologic significance of the bacterial-mammalian receptor interaction.
In the Borrelia work, we have two main projects ongoing in the lab. In one, we are trying to understand the mechanisms behind the requirement for the B. burgdorferi protein, P66, for the bacteria to cause infection in mammals. P66 binds to mammalian cell surface receptors called integrins and serves as a porin in the bacterial outer membrane. We know that the integrin binding function is important for the bacteria to cross endothelial layers and disseminate to different sites in the body. In another Borrelia project, we developed a new experimental model to determine the roles of bacterial adhesive proteins in how the bacteria colonize different tissues in mammals, and how they survive the mammalian defenses in the bloodstream.
Figure 1. This image is an Ixodes scapularis tick. Shown is the nymphal stage of the tick; the scale bar is 1 mm so these ticks are tiny. These ticks are important in transmitting Borrelia burgdorferi to new host animals, and sometimes to humans.
Figure 2: B. burgdorferi producing a red fluorescent protein in a dispersed tick midgut.
In the Leptospira work, we also focus in how the bacteria interact with endothelial cells. In severe cases of leptospirosis, widespread endothelial damage is seen, and this is associated with hemorrhage. L. interrogans binds to an endothelial cell surface receptor called VE-cadherin, which helps the endothelial cells form cell-cell junctions that maintain the integrity of small blood vessels. We are currently determining how the bacteria disrupt cadherin-cadherin interactions, and determining whether the bacterial proteins that bind VE-cadherin are responsible for the endothelial disruption caused by the bacteria. In a second Leptospira project, we are working to identify the bacterial proteins that help the bacteria bind to kidney cells, as the kidneys are where the bacteria reside in a chronically infected animal and from where they are released into the environment.
Figure 3: Leptospira interrogans (red) binding to human endothelial cells. An endothelial cell surface receptor for L. interrogans, VE-cadherin, is stained in green, but the cell-cell junctions are mostly disrupted. The endothelial cell nuclei are stained in blue.