The role of the mammalian host-state induced Borrelia burgdorferi lipoproteins in colonization and persistence in mice : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
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College Station, Tex. :
Texas A&M University System Health Science Center,
2008.
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| Abstract: | ABSTRACT: To determine which genes Borrelia burgdorferi utilized during the mammalian phase of infection, investigators have analyzed the transcriptional profile of B. burgdorferi using conditions that mimic the mammalian host-state. These analyses provided a subset of genes that include bbk32 and dbpBA. The working hypothesis tested herein is that B. burgdorferi genes that are induced under mammalian host conditions are necessary for optimal mammalian infection. With the advent of genetic systems for infectious B. burgdorferi, we tested how the inactivation of selected genes affected borrelial pathogenesis. Specifically, we isolated mutants, either individually or collectively, in bbk32 or dbpBA, as well as individual mutants in genes of unknown function, including bba04, bba32 and bba61. The results indicate that dbpBA are required for infectivity of mice as both the [delta]dbpBA::gent[superscript]R, bbk32::str[superscript]R and the [delta]dbpBA::gent[superscript]R strains did not infect mice, a phenotype which was restored by complementation with dbpBA. The [delta]dbpBA::gent[superscript]R mutant exhibited a phenotype which was restored by complementation with dbpBA. The [delta]dbpBA::gent[superscript]R mutant exhibited a colonization defect as early as three days post infection, before the adaptive immune response develops and after low dose infection of SCID mice. These findings suggest that the inability to adhere to host decorin may promote clearance of B. burgdorferi, perhaps via innate immune mechanisms. Furthermore, following high dose infection of SCID mice the dbpBA mutant demonstrated a mild colonization defect, suggesting that adaptive immunity is also required for clearance of the [delta]dbpBA::gent[superscript]R mutant from immunocompetent mice. B. burgdorferi requires the lipoproteins DbpBA and BBK32 for optimal infectivity, but must tightly regulate the amount of DbpBA adn BBK32 produced as overexpression impairs the infectivity potential of B. burgdorferi. The clearance of the overexpressing strains correlated with the synthesis of these lipoproteins, as the clearance increased with higher doses, presumably due to enhanced humoral clearance. By analogy to ospC and dbpBA, which are induced under mammalian host conditions and have potent phenotypes when mutated, we investigated the roles of bba05, bba32 and bba61, genes that induced as ospC and dbpBA albeit to a lesser extent. The mutants conferred either undetectable or subtle infectivity defects, suggesting that the degree of induction correlates with the severity of the infectivity deficit observed. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Office of Research and Graduate Studies of The Texas A&M University System Health Science Center in partial fulfillment for the requirements for the degree of Doctor of Philosophy August 2008." Approved as to style and content by: Jon T. Skare, Magnus Hook, Garry L. Adams, James E. Samuel, John M. Quarles. |
| Physical Description: | xii, 157 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 137-154). |