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You searched for +publisher:"University of North Carolina" +contributor:("Melehani, Jason"). One record found.

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University of North Carolina

1. Melehani, Jason. Mechanisms and consequences of Staphylococcus aureus Leukocidin AB-mediated activation of the host NLRP3 inflammasome.

Degree: Pharmacology, 2016, University of North Carolina

The NLRP3 inflammasome is a critical innate immune sensor implicated in the pathogenesis of dozens of infectious and non-infectious diseases. Activation of the NLRP3 inflammasome causes IL-1β and IL-18 secretion and necrotic cell death. Staphylococcus aureus is a common cause of infections in humans. S. aureus produces a family of pore-forming toxins that are cytotoxic to human immune cells. One recently discovered pore-forming toxin, Leukocidin AB, is the focus of studies herein. Leukocidin AB is a human-specific, pore-forming toxin that binds CD11b to initiate pore formation. In order to characterize the mechanism of Leukocidin AB cytotoxicity and determine its significance, we evaluated the effects of Leukocidin AB on primary human monocytes and THP1 monocytic cells. Leukocidin AB was one of the most potent toxins in killing primary human monocytes. In THP1 cells, knockdown of NLRP3 or ASC by shRNA diminished Leukocidin AB-induced cytotoxicity and prevented secretion of IL-1β and IL-18. We also characterized the NLRP3 inflammasome in bacterial survival during phagocytosis. When S. aureus was phagocytosed by THP1 cells, LukAB triggered IL-1β secretion and cell death. shRNA-mediated depletion of NLRP3 or ASC suppressed IL-1β secretion but had no effect on Leukocidin AB-induced cell death. These data suggest that a separate mechanism is responsible for triggering cell death when Leukocidin AB binds CD11b on the phagosome membrane instead of the plasma membrane. We also initiated studies to characterize the role of kinases and phosphorylation in the response to Leukocidin AB. Using multiplex inhibitor bead chromatography and quantitative mass spectrometry, we identified eight kinases that rapidly decrease in activity during Leukocidin AB exposure. We demonstrated a role for Death-Associated Protein Kinase in the response to Leukocidin AB by showing that its inhibition suppressed Leukocidin AB-induced cytokine secretion and cytotoxicity. And finally, we used a novel transfection method for overexpressing mutant proteins in THP1 cells to show that the NLRP3 S198D/S201D mutant could spontaneously activate NLRP3 inflammasome signaling. In total, these studies make significant contributions to the understanding of S. aureus pathogenesis and the regulation of innate immune NLRP3 inflammasome signaling in response to a human specific, S. aureus pore-forming toxin. Advisors/Committee Members: Melehani, Jason, Duncan, Joseph, Nicholas, Robert, Doerschuk, Claire, Willis, Monte, Johnson, Gary.

Subjects/Keywords: School of Medicine; Department of Pharmacology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Melehani, J. (2016). Mechanisms and consequences of Staphylococcus aureus Leukocidin AB-mediated activation of the host NLRP3 inflammasome. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:f98e7df6-408e-40db-8202-8ab65dd52e01

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Melehani, Jason. “Mechanisms and consequences of Staphylococcus aureus Leukocidin AB-mediated activation of the host NLRP3 inflammasome.” 2016. Thesis, University of North Carolina. Accessed October 26, 2020. https://cdr.lib.unc.edu/record/uuid:f98e7df6-408e-40db-8202-8ab65dd52e01.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Melehani, Jason. “Mechanisms and consequences of Staphylococcus aureus Leukocidin AB-mediated activation of the host NLRP3 inflammasome.” 2016. Web. 26 Oct 2020.

Vancouver:

Melehani J. Mechanisms and consequences of Staphylococcus aureus Leukocidin AB-mediated activation of the host NLRP3 inflammasome. [Internet] [Thesis]. University of North Carolina; 2016. [cited 2020 Oct 26]. Available from: https://cdr.lib.unc.edu/record/uuid:f98e7df6-408e-40db-8202-8ab65dd52e01.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Melehani J. Mechanisms and consequences of Staphylococcus aureus Leukocidin AB-mediated activation of the host NLRP3 inflammasome. [Thesis]. University of North Carolina; 2016. Available from: https://cdr.lib.unc.edu/record/uuid:f98e7df6-408e-40db-8202-8ab65dd52e01

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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