Abstract
The Lyme disease spirochete Borrelia burgdorferi sensu lato can cause a multitude of clinical manifestations because of its ability to disseminate into any organ system via migration through soft tissue, the lymphatic system, and the circulatory system. The latter is believed to constitute the predominant pathway for dissemination to distal sites from the inoculating tick bite. In spite of its importance, the hematogenous dissemination process remains largely uncharacterized, particularly due to difficulties studying this process in a living host and the lack of an in vitro system that recapitulates animal infection. In the current work, we provide the first information regarding the stage of the vascular transmigration pathway where three important adhesins function during invasion of mouse knee joint peripheral tissue from postcapillary venules. Using intravital imaging coupled with genetic experiments employing sequential double infection, we show a complex temporal choreography of P66, decorin binding proteins (DbpA/B), and outer surface protein C (OspC) at discrete steps along the pathway of vascular escape, underscoring the importance of B. burgdorferi adhesins in hematogenous dissemination in the mouse knee joint and the complexity of vascular transmigration by a disseminating pathogen. IMPORTANCE Lyme disease is caused by the spirochete Borrelia burgdorferi, which is transmitted by a bite from an infected tick. Disease development involves a complex series of host-pathogen interactions as well as dissemination of the infecting organisms to sites distal to the original tick bite. The predominant pathway for this is believed to be hematogenous dissemination. The mechanism by which the spirochetes escape circulation is unknown. Here, using intravital microscopy, where the Lyme spirochete can be observed in a living mouse, we have studied the stage in the vascular escape process where each of three surface adhesins functions to facilitate escape of the spirochete from postcapillary venules to invade mouse knee joint peripheral tissue. A complex pattern of involvement at various locations in the multistage process is described using a unique experimental approach that is applicable to other disseminating pathogens.