Molecular mechanisms involved in vascular interactions of the Lyme disease pathogen in a living host.
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 fo...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2008-10-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1000169&type=printable |
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| author | M Ursula Norman Tara J Moriarty Ashley R Dresser Brandie Millen Paul Kubes George Chaconas |
| author_facet | M Ursula Norman Tara J Moriarty Ashley R Dresser Brandie Millen Paul Kubes George Chaconas |
| author_sort | M Ursula Norman |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-61391a39b2ec4003a677f0f948ac31fd |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2008-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-61391a39b2ec4003a677f0f948ac31fd2025-08-20T03:22:26ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742008-10-01410e100016910.1371/journal.ppat.1000169Molecular mechanisms involved in vascular interactions of the Lyme disease pathogen in a living host.M Ursula NormanTara J MoriartyAshley R DresserBrandie MillenPaul KubesGeorge ChaconasHematogenous 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1000169&type=printable |
| spellingShingle | M Ursula Norman Tara J Moriarty Ashley R Dresser Brandie Millen Paul Kubes George Chaconas Molecular mechanisms involved in vascular interactions of the Lyme disease pathogen in a living host. PLoS Pathogens |
| title | Molecular mechanisms involved in vascular interactions of the Lyme disease pathogen in a living host. |
| title_full | Molecular mechanisms involved in vascular interactions of the Lyme disease pathogen in a living host. |
| title_fullStr | Molecular mechanisms involved in vascular interactions of the Lyme disease pathogen in a living host. |
| title_full_unstemmed | Molecular mechanisms involved in vascular interactions of the Lyme disease pathogen in a living host. |
| title_short | Molecular mechanisms involved in vascular interactions of the Lyme disease pathogen in a living host. |
| title_sort | molecular mechanisms involved in vascular interactions of the lyme disease pathogen in a living host |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1000169&type=printable |
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