{"@context":"http://iiif.io/api/presentation/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/manifest.json","@type":"sc:Manifest","label":"Contributions of the inhibitor of kappa B kinases (IKKs) in macrophages and neutrophils after Francisella tularensis live vaccine strain (LVS) infection.","metadata":[{"label":"dc.description.sponsorship","value":"This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree."},{"label":"dc.format","value":"Monograph"},{"label":"dc.format.medium","value":"Electronic Resource"},{"label":"dc.identifier.uri","value":"http://hdl.handle.net/1951/55614"},{"label":"dc.language.iso","value":"en_US"},{"label":"dc.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.abstract","value":"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."},{"label":"dcterms.available","value":"2015-04-24T14:53:06Z"},{"label":"dcterms.contributor","value":"Hadjiargyrou, Michael"},{"label":"dcterms.creator","value":"Samaniego, Sylvia"},{"label":"dcterms.dateAccepted","value":"2012-05-15T18:06:45Z"},{"label":"dcterms.dateSubmitted","value":"2015-04-24T14:53:06Z"},{"label":"dcterms.description","value":"Department of Genetics"},{"label":"dcterms.format","value":"Application/PDF"},{"label":"dcterms.identifier","value":"http://hdl.handle.net/1951/55614"},{"label":"dcterms.issued","value":"2010-12-01"},{"label":"dcterms.language","value":"en_US"},{"label":"dcterms.provenance","value":"Made available in DSpace on 2012-05-15T18:06:45Z (GMT). No. of bitstreams: 1\nSamaniego_grad.sunysb_0771E_10356.pdf: 6584022 bytes, checksum: 5c07249060715321c44bb3f6c3024117 (MD5)\n  Previous issue date:    1"},{"label":"dcterms.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.subject","value":"Francisella, IKK, LVS"},{"label":"dcterms.title","value":"Contributions of the inhibitor of kappa B kinases (IKKs) in macrophages and neutrophils after Francisella tularensis live vaccine strain (LVS) infection."},{"label":"dcterms.type","value":"Dissertation"},{"label":"dc.type","value":"Dissertation"}],"description":"This manifest was generated dynamically","viewingDirection":"left-to-right","sequences":[{"@type":"sc:Sequence","canvases":[{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json","@type":"sc:Canvas","label":"Page 1","height":1650,"width":1275,"images":[{"@type":"oa:Annotation","motivation":"sc:painting","resource":{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/32%2F52%2F86%2F32528654751251754059319428201536536750/full/full/0/default.jpg","@type":"dctypes:Image","format":"image/jpeg","height":1650,"width":1275,"service":{"@context":"http://iiif.io/api/image/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/32%2F52%2F86%2F32528654751251754059319428201536536750","profile":"http://iiif.io/api/image/2/level2.json"}},"on":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json"}]}]}]}