Grant: Project Grant

Blood-borne spread of bacteria via the cardiovascular system (dissemination) is responsible for most death due to bacterial infection. A key dissemination step is bacterial adhesion to the cells lining blood vessels (endothelial cells), which permits bacteria to slow down and escape from the bloodstream to infect new tissues. Bacterial interaction with blood vessels is challenging due to the force generated by flowing blood. Defining the physical mechanisms allowing bacteria to stick to blood vessel surfaces under flow is crucial for understanding how bacteria disseminate, and may lead to the development of strategies for slowing or preventing bacterial dissemination. However, the vascular adhesion mechanisms of most pathogens are largely unknown. The bacterium that causes Lyme disease, Borrelia burgdorferi, is a highly invasive pathogen that disseminates to most organs and tissues. Blood vessel and flow properties vary widely in different tissues and organs, generating unique, postal code-like conditions in each vascular bed that affect how bacteria disseminate to these tissues. Since B. burgdorferi disseminates to many tissues this pathogen may produce many adhesion molecules facilitating vascular interactions under diverse conditions. Vascular interaction mechanisms are better-understood for B. burgdorferi than most other pathogens, largely because we and collaborators have developed powerful methods to study dissemination in living mice and artificial systems mimicking blood vessels. We have identified several Borrelia, endothelial cell and blood molecules contributing to B. burgdorferi-endothelial interactions, although many molecules and mechanisms supporting B. burgdorferi dissemination to different tissues remain unknown. These studies will examine the repertoire of molecules and mechanisms supporting Borrelia dissemination to diverse tissues, and will provide the groundwork for exploring dissemination mechanisms of other bacterial pathogens.