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dc.contributor.authorMeghil, Mohameden
dc.date.accessioned2019-08-12T13:00:34Zen
dc.date.available2019-08-12T13:00:34Zen
dc.date.issued05-2019en
dc.identifier.urihttp://hdl.handle.net/10675.2/622582en
dc.descriptionEmbargoed until 08/12/2021en
dc.description.abstractPerturbation of fundamental processes of immune homeostasis, such as apoptosis and autophagy, can result in dire consequences such as autoimmune diseases. Periodontitis is an inflammatory oral disease that is characterized by oral microbial dysbiosis, and deregulation of the host immune response. The aim of this study was to elucidate the underlying mechanisms by which Porphyromonas gingivalis (P. gingivalis) manipulates dendritic cell (DC) signaling to perturb immune homeostasis. Using a combination of Western blotting, flow cytometry, qRT-PCR and immunofluorescence analysis, we show a pivotal role for the minor (Mfa1) fimbriae of P. gingivalis in nuclear/cytoplasmic shuttling of Akt and FOXO1. Mfa1-induced Akt nuclear localization and activation ultimately induced mTOR. The upregulated Akt/mTOR axis was shown to downregulate the intracellular levels of LC3II, an autophagy protein also designated Atg8, required for autophagosome formation and maturation. Further studies utilizing the allosteric panAkt inhibitor MK2206 and rapamycin an mTOR inhibitor confirmed that the activation of Akt/mTOR signaling by P. gingivalis inhibited autophagy in DCs. Concomitant with inhibiting autophagy, we show a pivotal role for Mfa1 fimbriated P. gingivalis in induction of the antiapoptotic protein BCL2, decreased caspase-3 cleavage and decreased expression of pro-apoptotic proteins Bax and Bim in infected DCs, ultimately blocking programmed death of infected DC cells. Importantly, we show that, by using ABT-199 peptide to disrupt interaction of antiapoptotic BCL2 and its proapoptotic partners BAK/BAX, we can restore programmed cell death to P. gingivalis-infected DC cells. In summary, we have identified the underlying mechanism utilized by P. gingivalis to promote the survival of its host immune cells while preventing its own autophagic elimination.en
dc.publisherAugusta Universityen
dc.subjectDentistryen
dc.titleThe Influence of Porphyromonas gingivalis Fimbrial Expression on Human Dendritic Cell Signaling and Innate Immune Homeostatic Functionsen
dc.typedissertationen
dc.contributor.departmentBiomedical Sciencesen
dc.language.rfc3066enen
dc.date.updated2019-08-12T13:00:35Zen
dc.description.advisorCutler, Christopher Wen
dc.description.degreeDoctor of Philosophyen
dc.description.committeeYeudall, Andrewen
dc.description.committeeFulton, Daviden
dc.description.committeeDhandapani, Krishnanen
dc.description.committeeThompson, Stuarten
dc.description.embargo08/12/2021en


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