Muruve, DanielBondzi-Simpson, Nana Adom2018-02-132018-02-132018-01-08http://hdl.handle.net/1880/106395Enterohemorrhagic Escherichia coli (EHEC) is a pathogen that causes severe colitis. Shiga toxins (Stx) are a major virulence factor for EHEC and Stx-induced inflammation and cell death play a critical role in the development of EHEC-related disease. Therefore, the goal of this project was to examine the mechanisms by which Stx activates proinflammatory cytokine IL-1β and cell death in human macrophages. Stx induced ROS-dependent IL-1β secretion and pyroptosis in human THP-1 macrophages but not murine macrophages that lacked the Stx receptor CD77. Stx triggered the assembly of NLRP3, ASC and caspase-1 containing inflammasomes and genetic deletion of NLRP3 abolished Stx-induced IL-1β maturation and pyroptosis. Stx preferentially induced expression the endoplasmic reticulum stress receptor IRE1α. Pharmacological inhibition of IRE1α significantly reduced Stx-induced mitochondrial ROS production, IL-1β, and pyroptosis. These data suggest that Stx activate the IRE1α arm of the ER stress pathway upstream of mitochondrial ROS to trigger the NLRP3 inflammasome.engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.Immunologymaster thesis10.11575/PRISM/5472