Entamoeba histolytica-induced Activation of the NLRP3 Inflammasome
Date
2015-09-18
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Abstract
The focus of my research has been the molecular activation and regulation of the NLRP3 inflammasome. The NLRP3 inflammasome is an intracellular innate immune sensor that promotes highly inflammatory responses during infection and tissue injury. NLRP3 belongs to a family of intracellular innate immune sensors that activate a proteolyic cascade driven by caspase-1, which leads to processing and release of interleukin (IL)-1β, IL-18 as well as several other pro-inflammatory cytokines and often triggers a form of lytic cell death known as pyroptosis. My studies address two questions: 1) how the invasive protozoan pathogen Entamoeba histolytica, the disease-causing agent of amebiasis, activates the NLRP3 inflammasome and 2) how prostaglandin E2 (PGE2) rapidly switches-off the NLRP3 inflammasome. Amebiasis is among the three top causes of death from parasitic infections worldwide, as a result of amebic colitis (dysentery) and liver or brain abscess. When E. histolytica invades the intestinal barrier and contacts host tissue there is a profound inflammatory response, which is thought to drive the disease. One of the central outstanding questions has been how the immune response is escalated at sites of invasion. Adherence of the parasite to host cells has long been appreciated in the pathogenesis of amebiasis, but was never considered as a “cue” that host cells use to detect E. histolytica and initiate host defense. We introduce the idea and demonstrate that an intercellular junction forms between E. histolytica and host cells upon contact that engages the NLRP3 inflammasome. For NLRP3 to be effective during an inflammatory response it must be tightly regulated once it has become active. By setting limits on the magnitude and duration of pro-inflammatory signaling the degree of by-stander damage generated during inflammation is reduced and enables the acute inflammatory response to
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progress into a stage of resolution, repair and eventual termination. Prostaglandin E2 (PGE2) is
one of the major lipid mediators produced at sites of inflammation that balances and regulates the progression of inflammatory responses. We identified PGE2 signaling via EP4 receptor-cAMP-PKA pathway is a molecular switch that inhibits assembly and activation of the NLRP3 inflammasome.
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Microbiology
Citation
Mortimer, L. (2015). Entamoeba histolytica-induced Activation of the NLRP3 Inflammasome (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/25913