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dc.contributor.advisorMarcu, Kenneth B.; Hadjiargyrou, Michaelen_US
dc.contributor.authorSamaniego, Sylviaen_US
dc.contributor.otherDepartment of Geneticsen_US
dc.date.accessioned2012-05-15T18:06:45Z
dc.date.available2012-05-15T18:06:45Z
dc.date.issued1-Dec-10en_US
dc.date.submittedDec-10en_US
dc.identifierSamaniego_grad.sunysb_0771E_10356.pdfen_US
dc.identifier.urihttp://hdl.handle.net/1951/55614
dc.description.abstractThe immune system is a complex network of cells regulated by a number of signaling pathways to drive specific host defenses against invading pathogens. The NF-&kappaB (nuclear factor of the kappa light chain enhancer in B cells) family of inducible transcription factors is a critical regulator of many innate and adaptive immune responses. NF-&kappaB activation by several receptors converges upon two upstream kinases, IKK&alpha and IKK&beta, that regulate gene induction. Many studies report that IKK&beta is the critical kinase involved in NF--&kappaB activation, although at a transcriptional level, both kinases are needed to obtain the full spectrum of gene induction. More recently, in an in vivo bacterial infection model both IKK&alpha and IKK&beta were reported to have anti-inflammatory properties through different mechanisms.The intracellular bacterium Francisella tularensis is able to down modulate inflammatory reactions within macrophages and neutrophils to provide a niche for bacterial growth. To this end, I asked whether disruptions of NF-&kappaB signaling, specifically through IKK&alpha and IKK&beta, could promote inflammation and allow the host more resistance to infection.I used conditional gene targeting of IKK&alpha and IKK&beta to generate mice with specific deletions for either kinase in these cells. These mice were used in a tularemia infection using the live vaccine strain of Francisella tularensis (Ft. LVS) as a model to elucidate the specific contributions of each kinase.Contrary to what has been previously reported for Group B Streptococcus infection models, IKK&beta but not IKK&alpha, was required for host resistance and survival in tularemia infection as 100% of Ft. LVS infected mice succumbed to lethal infection within 10 days.In a sublethal model of infection, both IKK&alpha and IKK&beta contributed in different ways to the maintenance of hepatic granulomas after infection. Depletion of IKK&alpha led to fewer, but sometimes, large necrotic granuloma formation indicating a potential role for IKK&alpha in the clearance of apoptotic cells. IKK&beta depletion resulted disordered granuloma structures and elevated bacterial colonization and growth throughout the infection. This led to increased inflammation as early as 2 days post infection as evidenced by a polarization towards M1 macrophages and IL-12 production. Compensation mechanisms to reduce inflammation such as an increase in myeloid derived suppressor cells or a subsequent M2a macrophage polarization occurred, but were not able to control inflammation or bacterial growth in these mice. In addition, IKK&beta loss resulted in protracted IFN-&gamma production by cytotoxic T lymphocytes.Overall, in an Ft. LVS infection model, IKK&alpha may be more important in neutrophils for the clearance of apoptotic cells, while IKK&beta is required more globally to prevent inflammation and control bacterial colonization that cannot be compensated by anti-inflammatory mechanisms. These functions appear to be correlated with early activation of both macrophages, neutrophils and extrinsic activation of cytotoxic T lymphocytes.en_US
dc.description.sponsorshipStony Brook University Libraries. SBU Graduate School in Department of Genetics. Lawrence Martin (Dean of Graduate School).en_US
dc.formatElectronic Resourceen_US
dc.language.isoen_USen_US
dc.publisherThe Graduate School, Stony Brook University: Stony Brook, NY.en_US
dc.subject.lcshGeneticsen_US
dc.subject.otherFrancisella, IKK, LVSen_US
dc.titleContributions of the inhibitor of kappa B kinases (IKKs) in macrophages and neutrophils after Francisella tularensis live vaccine strain (LVS) infection.en_US
dc.typeDissertationen_US
dc.description.advisorAdvisor(s): Kenneth B. Marcu. Michael Hadjiargyrou. Committee Member(s): Martha B. Furie; Richard R. Kew; William P. Tansey.en_US
dc.mimetypeApplication/PDFen_US


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