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ndltd-OhioLink-oai-etd.ohiolink.edu-osu1195584597
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu11955845972021-08-03T05:52:50Z Molecular mechanisms of host cell response to Francisella infection Parsa Venkata, Laxmi Kishore Francisella tularensis is a Gram-negative intra-cellular pathogen causing the zoonotic disease tularemia. The mechanisms of host response to infection are poorly understood. Francisella tularensis is considered a potential bio-weapon. Thus, currently there is an increased focus to understand the regulatory mechanisms controlling the host response and the strategies employed by the pathogen to evade the host-mounted immune response. In this study, we examined the molecular mechanisms of i) phagocytosis of Francisella ii) inflammatory response to infection and iii) subversion mechanisms employed by Francisella against host IFNgamma response. In the first part of this dissertation we have identified the intracellular tyrosine kinase Syk as a critical player in the engulfment of Francisella and the subsequent cytokine release. Specifically, we established that Syk promotes Francisella phagocytosis and the ensuing cytokine response via the activation of Erk and PI3K/Akt pathways. Unchecked cytokine production is deleterious to the host thus emphasizing the importance of negative regulators. Therefore, in the second part of this dissertation, we focused on identifying negative regulators of host cell response. These studies revealed that the inositol phosphatase SHIP1 although dispensable for Francisella phagocytosis, is critical for regulating pro- and anti-inflammatory mediator release in response to infection. Molecular analyses of SHIP1-dependent cytokine regulation demonstrated that SHIP1 suppresses the activation of PI3K/Akt/NFkB signaling cascade. Cytokines produced during infection confer protection against infection. One major mechanism of cytokine-mediated host protection is through the induction NK cell and T cell IFNgamma production, which in turn protects against infection by limiting phagosomal escape of the organisms. However, some pathogens are known to subvert this host-protective response. In the third part of this project, we examined whether Francisella subverts IFNgamma signaling response. Here, we established that Francisella suppresses IFNgamma-induced host response through the upregulation of a negative regulator, SOCS3. Functional analysis revealed that Francisella infection inhibits IFNgamma-induced iNOS, a critical anti-microbial enzyme, leading to the enhanced intra-macrophage survival of the bacteria. Collectively, these studies unravel signaling pathways that modulate host response against Francisella infection and identify potential targets for future therapeutic interventions. 2007-12-10 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1195584597 http://rave.ohiolink.edu/etdc/view?acc_num=osu1195584597 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
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NDLTD
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| language |
English
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NDLTD
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| author |
Parsa Venkata, Laxmi Kishore
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| spellingShingle |
Parsa Venkata, Laxmi Kishore
Molecular mechanisms of host cell response to Francisella infection
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| author_facet |
Parsa Venkata, Laxmi Kishore
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| author_sort |
Parsa Venkata, Laxmi Kishore
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| title |
Molecular mechanisms of host cell response to Francisella infection
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| title_short |
Molecular mechanisms of host cell response to Francisella infection
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| title_full |
Molecular mechanisms of host cell response to Francisella infection
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| title_fullStr |
Molecular mechanisms of host cell response to Francisella infection
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| title_full_unstemmed |
Molecular mechanisms of host cell response to Francisella infection
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| title_sort |
molecular mechanisms of host cell response to francisella infection
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The Ohio State University / OhioLINK
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2007
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| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1195584597
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| work_keys_str_mv |
AT parsavenkatalaxmikishore molecularmechanismsofhostcellresponsetofrancisellainfection
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| _version_ |
1719427064357978112
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