Modulation of polymorphonuclear leukocyte function during Coxiella burnetii infection : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
| Published: |
[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2010]
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| Subjects: |
| Abstract: | ABSTRACT: Coxiella burnetii, the etiological agent of Q fever, is a small gram-negative, obligate intracellular bacteria. Replication during infection has been shown to be inhibited by oxidative stress using p47[phox-/-] and iNOS[-/-] mice in vivo and by pharmacologic inhibitors in vitro. Building upon this model, we investigated the role polymorphonuclear leukocytes (PMN) play in control of infection, since the NAPH-oxidase mediated release of reactive oxygen intermediates (ROI) is the primary bactericidal mechanism for these cells which are critical for early innate clearance. To assess the role of PMN in control of C. burnetii challenge in vivo, we used mice depleted of PMN through the administration of the monoclonal antibody RB6-8C5. PMN depleted mice had larger spleens, more hepatic granulomas and higher C. burnetii genome copies in their spleen than non-depleted animals. In vitro infection with C. burnetii did not stimulate secretion of the major PMN chemokine IL-8 or the proinflammatory cytokine TNF-[alpha]. Earlier studies suggested C. burnetii actively inhibit release of ROI from PMN through expression of an undefined acid phosphatase (Acp). Recent genomic annotations identified one open reading frame (CBU0335) which may encode a Sec-and type II-dependent secreted Acp. To test this model, viable C. burnetii (both tissue culture propagated and extracellular media grown), secretion extracts or purified recombinant Acp (rAcp) were combined with human PMN induced with PMA. The release of ROI was inhibited when PMNs were challenged with viable C. burnetii, secretion extracts or rAcp, but not when challenged with electron beam-inactivated C. burnetii. C. burnetii secretion extracts or rAcp were also able to inhibit PMA-induced formation of NADPH oxidase complex on PMA membranes, suggesting a molecular mechanism responsible for this inhibition. These data support a model in which C. burnetii eludes the primary ROI killing mechanism of PMN by secreting at least one acid phosphatase enzyme. |
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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 of the requirements for the degree of Doctor of Philosophy May 2010." Approved as to style and content by: James E. Samuel, Vernon Tesh, Jon T. Skare, Jeffery D. Cirillo, John M. Quarles. |
| Physical Description: | viii, 96 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 84-95). |