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The dual role of the Plasminogen Activation System in the dissemination of Borrelia burgdorferi and the inflammatory migration of immune cells

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dc.contributor.advisor Benach, Jorge L en_US
dc.contributor.author Haile, Woldeab Berhane en_US
dc.contributor.other Department of Molecular and Cellular Biology en_US
dc.date.accessioned 2017-09-20T16:50:19Z
dc.date.available 2017-09-20T16:50:19Z
dc.date.issued 2006-08-01
dc.identifier.uri http://hdl.handle.net/11401/76464 en_US
dc.description 149 pg. en_US
dc.description.abstract Lyme disease is the most common vector borne disease in the United States. It is caused by a spirochete, Borrelia burgdorferi. One of the aspects of Borrelia infection that has been the focus of investigation is its dissemination from its site of entry to the secondary infectious sites to become systemic. It has previously been shown that B. burgdorferi interacts with the mammalian plasminogen activation system (PAS). In this dissertation, I further investigated the interaction of B. burgdorferi with the PAS. I showed that Borrelia induces urokinase plasminogen activator (uPA) and its physiological inhibitors, plasminogen activator inhibitors 1 and 2 (PAI-l and PAI-2). Induction of uPA resulted in increased penetration of B. burgdorferi across extracellular matrix (ECM) components. Using transmigration assays, I showed that the direct coincubation of B. burgdorferi with monocytic cells, Mono Mac 6 (MM6) cells, and peripheral blood monocytes, enhances bacterial invasion across a barrier coated with fibronectin, mediated by uPA. Moreover, PAI-2 does not have a significant effect on the uPA-potentiated transmigration of B. burgdorferi, showing that bacterial invasion is not hampered by the inhibitor. Using invasion and adhesion assays of two different monocytic cell lines. MM6 and THP-1, I also showed that the interaction of B. burgdorferi with the PAS profoundly affects the invasive ability of monocytic cells due to the induction of PAI-2 by decreasing the adhesive and migratory capacity of the cells. Kinetic studies of the inductions of these proteins revealed that uPA and PAI-2 inductions are temporally modulated to benefit the pathogen in a twofold way. First, the early induction of uPA ensures sufficient time for uPA to bind to the bacteria before it is permanently inhibited by PAI-2. Second, although PAI-2 is induced after uPA, it is induced early enough to inhibit monocyte invasion. Finally, using uPAR deficient mice, it was shown that dissemination of bacteria and the inflammatory infiltration of immune cells were not different in this phenotype. Overall this dissertation showed that the PAS plays a two fold role in the pathogenesis of B. burgdorferi infection, both by enhancing bacterial dissemination and by diminishing host-cell inflammatory migration. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Microbiology -- Immunology en_US
dc.subject.other Borrelia, Monocytes, PAI-2, Plasminogen, uPA en_US
dc.title The dual role of the Plasminogen Activation System in the dissemination of Borrelia burgdorferi and the inflammatory migration of immune cells en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Furie, Martha B en_US
dc.contributor.committeemember Bliska, James B en_US
dc.contributor.committeemember Ghebrehiwet, Berhane en_US
dc.contributor.committeemember Kew, Richard R. en_US

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