title: Vascular binding of a pathogen under shear force through mechanistically distinct sequential interactions with host macromolecules.
abstract: Systemic dissemination of microbial pathogens permits microbes to spread from the initial site of infection to secondary target tissues and is responsible for most mortality due to bacterial infections. Dissemination is a critical stage of disease progression by the Lyme spirochaete, Borrelia burgdorferi. However, many mechanistic features of the process are not yet understood. A key step is adhesion of circulating microbes to vascular surfaces in the face of the shear forces present in flowing blood. Using real-time microscopic imaging of the Lyme spirochaete in living mice we previously identified the first bacterial protein (B. burgdorferi BBK32) shown to mediate vascular adhesion in vivo. Vascular adhesion is also dependent on host fibronectin (Fn) and glycosaminoglycans (GAGs). In the present study, we investigated the mechanisms of BBK32-dependent vascular adhesion in vivo. We determined that BBK32-Fn interactions (tethering) function as a molecular braking mechanism that permits the formation of more stable BBK32-GAG interactions (dragging) between circulating bacteria and vascular surfaces. Since BBK32-like proteins are expressed in a variety of pathogens we believe that the vascular adhesion mechanisms we have deciphered here may be critical for understanding the dissemination mechanisms of other bacterial pathogens.
authors.affiliation: Matrix Dynamics Group, and Department of Laboratory Medicine and Pathobiology, University of Toronto, ON M5S 3E2, Canada. tara.moriarty@utoronto.ca
authors.forename: Tara J
authors.initials: TJ
authors.lastname: Moriarty
authors.forename: Meiqing
authors.initials: M
authors.lastname: Shi
authors.forename: Yi-Pin
authors.initials: YP
authors.lastname: Lin
authors.forename: Rhodaba
authors.initials: R
authors.lastname: Ebady
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Tanya
authors.initials: T
authors.lastname: Odisho
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Hardy
authors.forename: Aydan
authors.initials: A
authors.lastname: Salman-Dilgimen
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Eric H
authors.initials: EH
authors.lastname: Weening
authors.forename: Jon T
authors.initials: JT
authors.lastname: Skare
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
authors.forename: John
authors.initials: J
authors.lastname: Leong
authors.forename: George
authors.initials: G
authors.lastname: Chaconas
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D025065:Borrelia burgdorferi / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000382:microbiology; D005353:Fibronectins / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D008193:Lyme Disease / Q000382:microbiology / Q000503:physiopathology; D051379:Mice; D011485:Protein Binding
chemical_list: D001426:Bacterial Proteins; D005353:Fibronectins; D006025:Glycosaminoglycans; C106209:p35 antigen, Borrelia