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      Molecular Mechanisms Involved in Vascular Interactions of the Lyme Disease Pathogen in a Living Host

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          Abstract

          Hematogenous dissemination is important for infection by many bacterial pathogens, but is poorly understood because of the inability to directly observe this process in living hosts at the single cell level. All disseminating pathogens must tether to the host endothelium despite significant shear forces caused by blood flow. However, the molecules that mediate tethering interactions have not been identified for any bacterial pathogen except E. coli, which tethers to host cells via a specialized pillus structure that is not found in many pathogens. Furthermore, the mechanisms underlying tethering have never been examined in living hosts. We recently engineered a fluorescent strain of Borrelia burgdorferi, the Lyme disease pathogen, and visualized its dissemination from the microvasculature of living mice using intravital microscopy. We found that dissemination was a multistage process that included tethering, dragging, stationary adhesion and extravasation. In the study described here, we used quantitative real-time intravital microscopy to investigate the mechanistic features of the vascular interaction stage of B. burgdorferi dissemination. We found that tethering and dragging interactions were mechanistically distinct from stationary adhesion, and constituted the rate-limiting initiation step of microvascular interactions. Surprisingly, initiation was mediated by host Fn and GAGs, and the Fn- and GAG-interacting B. burgdorferi protein BBK32. Initiation was also strongly inhibited by the low molecular weight clinical heparin dalteparin. These findings indicate that the initiation of spirochete microvascular interactions is dependent on host ligands known to interact in vitro with numerous other bacterial pathogens. This conclusion raises the intriguing possibility that fibronectin and GAG interactions might be a general feature of hematogenous dissemination by other pathogens.

          Author Summary

          Many bacterial pathogens can cause systemic illness by disseminating through the blood to distant target sites. However, hematogenous dissemination is still poorly understood, in part because of an inability to directly observe this process in living hosts in real time and at the level of individual pathogens. We recently engineered a fluorescent strain of Borrelia burgdorferi, the Lyme disease pathogen, and visualized its dissemination from the microvasculature of living mice using intravital microscopy. We found that dissemination was a multistage process that included tethering, dragging, stationary adhesion and extravasation. In the study described here, we used quantitative real-time intravital microscopy to investigate the mechanistic features of the vascular interaction stage of B. burgdorferi dissemination in living hosts. We found that tethering and dragging interactions (collectively referred to as initiation interactions) were mechanistically distinct from stationary adhesion. Initiation of microvascular interactions required the B. burgdorferi protein BBK32, and host ligands fibronectin and glycosaminoglycans. Initiation interactions were also strongly inhibited by the low molecular weight clinical heparin dalteparin. Since numerous bacterial pathogens can interact with fibronectin and glycosaminoglycans in vitro, these observations raise the intriguing possibility that fibronectin and glycosaminoglycan recruitment might be a feature of hematogenous dissemination by other pathogens.

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          Most cited references73

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          Leptospirosis: a zoonotic disease of global importance.

          In the past decade, leptospirosis has emerged as a globally important infectious disease. It occurs in urban environments of industrialised and developing countries, as well as in rural regions worldwide. Mortality remains significant, related both to delays in diagnosis due to lack of infrastructure and adequate clinical suspicion, and to other poorly understood reasons that may include inherent pathogenicity of some leptospiral strains or genetically determined host immunopathological responses. Pulmonary haemorrhage is recognised increasingly as a major, often lethal, manifestation of leptospirosis, the pathogenesis of which remains unclear. The completion of the genome sequence of Leptospira interrogans serovar lai, and other continuing leptospiral genome sequencing projects, promise to guide future work on the disease. Mainstays of treatment are still tetracyclines and beta-lactam/cephalosporins. No vaccine is available. Prevention is largely dependent on sanitation measures that may be difficult to implement, especially in developing countries.
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            Isolation and cultivation of Lyme disease spirochetes.

            A Barbour (1984)
            The successful isolation and cultivation of Lyme disease spirochetes traces its lineage to early attempts at cultivating relapsing fever borreliae. Observations on the growth of Lyme disease spirochetes under different in vitro conditions may yield important clues to both the metabolic characteristics of these newly discovered organisms and the pathogenesis of Lyme disease. Images FIG. 1
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              The role of heparan sulphate in inflammation.

              The polysaccharide heparan sulphate is ubiquitously expressed as a proteoglycan in extracellular matrices and on cell surfaces. Heparan sulphate has marked sequence diversity that allows it to specifically interact with many proteins. This Review focuses on the multiple roles of heparan sulphate in inflammatory responses and, in particular, on its participation in almost every stage of leukocyte transmigration through the blood-vessel wall. Heparan sulphate is involved in the initial adhesion of leukocytes to the inflamed endothelium, the subsequent chemokine-mediated transmigration through the vessel wall and the establishment of both acute and chronic inflammatory reactions.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                October 2008
                October 2008
                3 October 2008
                : 4
                : 10
                : e1000169
                Affiliations
                [1 ]Department of Physiology & Biophysics, University of Calgary, Calgary, Alberta, Canada
                [2 ]Departments of Biochemistry & Molecular Biology and Microbiology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
                Medical College of Wisconsin, United States of America
                Author notes
                [¤]

                Current address: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Victoria, Australia

                Conceived and designed the experiments: MUN TJM GC. Performed the experiments: MUN TJM ARD BM. Analyzed the data: MUN TJM GC. Wrote the paper: MUN TJM PK GC.

                Article
                08-PLPA-RA-0519R3
                10.1371/journal.ppat.1000169
                2542414
                18833295
                07ef471f-aec2-4eda-80c4-dc836a2f99b2
                Norman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 21 May 2008
                : 8 September 2008
                Page count
                Pages: 11
                Categories
                Research Article
                Infectious Diseases/Bacterial Infections
                Microbiology/Cellular Microbiology and Pathogenesis
                Microbiology/Medical Microbiology

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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