Matrix Dynamics Group, Faculty of Dentistry, University of Toronto
Vascular adhesion mechanisms of the Lyme disease spirochete
Blood-borne spread (dissemination) of pathogens is a critical step in the development of serious infectious disease, and is responsible for most of the mortality due to bacterial infection. The dissemination mechanisms of many bacterial pathogens are largely unknown. A key event in dissemination is pathogen adhesion to vascular endothelium, an event which permits circulating microbes to marginate from the bloodstream and decelerate sufficiently to transmigrate through the vasculature into target tissues. Vascular adhesion is strongly influenced by the significant fluid shear forces present in flowing blood.
My research focuses on the mechanisms used by the Lyme disease bacterium Borrelia burgdorferi (Bb) to disseminate in the bloodstream of its vertebrate host, a process which we can observe in real time and 3D space in living animals using intravital microscopy. My previous work determined that Bb vascular adhesion is mediated by the Bb lipoprotein BBK32, a molecule which interacts with host fibronectin, glycosaminoglycans and fibrinogen, and is conserved in other disseminating bacterial pathogens.
The objective of this proposal is to determine the mechanism of BBK32-regulated vascular adhesion. To do this, I will investigate the mechanisms of BBK32 interactions with target host molecules during shear force-regulated vascular adhesion of Bb. These studies will provide the first direct insight into the novel vascular adhesion mechanism of an extracellular bacterial pathogen in real-time and space, and will identify adhesion mechanisms which could be useful for the identification of dissemination-inhibiting therapeutic reagents.