| dc.identifier.uri | http://hdl.handle.net/1951/55614 | |
| dc.identifier.uri | http://hdl.handle.net/11401/72662 | |
| 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 | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | The 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. | |
| dcterms.available | 2012-05-15T18:06:45Z | |
| dcterms.available | 2015-04-24T14:53:06Z | |
| dcterms.contributor | Martha B. Furie | en_US |
| dcterms.contributor | Marcu, Kenneth B. | en_US |
| dcterms.contributor | Richard R. Kew | en_US |
| dcterms.contributor | Hadjiargyrou, Michael | en_US |
| dcterms.contributor | William P. Tansey. | en_US |
| dcterms.creator | Samaniego, Sylvia | |
| dcterms.dateAccepted | 2012-05-15T18:06:45Z | |
| dcterms.dateAccepted | 2015-04-24T14:53:06Z | |
| dcterms.dateSubmitted | 2012-05-15T18:06:45Z | |
| dcterms.dateSubmitted | 2015-04-24T14:53:06Z | |
| dcterms.description | Department of Genetics | en_US |
| dcterms.format | Monograph | |
| dcterms.format | Application/PDF | en_US |
| dcterms.identifier | http://hdl.handle.net/1951/55614 | |
| dcterms.identifier | Samaniego_grad.sunysb_0771E_10356.pdf | en_US |
| dcterms.identifier | http://hdl.handle.net/11401/72662 | |
| dcterms.issued | 2010-12-01 | |
| dcterms.language | en_US | |
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| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Genetics | |
| dcterms.subject | Francisella, IKK, LVS | |
| dcterms.title | Contributions of the inhibitor of kappa B kinases (IKKs) in macrophages and neutrophils after Francisella tularensis live vaccine strain (LVS) infection. | |
| dcterms.type | Dissertation | |
