The Role of NLRP3 in Modulating Innate Immune Responses against Francisella tularensis
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Issue Date
2016
Authors
Westcott, Elizabeth Leigh '16
Degree
MS in Pharmaceutical Sciences
Advisor
Malik, Meenakshi
Committee Members
Goodman-Snitkoff, Gail
Dearborn, Richard
Yager, Eric
Dearborn, Richard
Yager, Eric
Journal Title
Journal ISSN
Volume Title
Abstract
Francisella tularensis is a gram-negative intracellular pathogen and the causative agent of a fatal zoonotic disease known as tularemia. Due to its high virulence, ease of aerosolization, and use in bioweapon programs in the past, the Centers for Disease Control have classified F. tularensis as a Category A select agent. Owing to its significant intracellular lifecycle, F. tularensis is likely detected by cytosolic innate immune sensors such as Nod-like receptors (NLRs) which are activated in response to specific microbial or host cell damage signals. Stimulated NLRs assemble into a multiprotein complex termed the inflammasome leading to the downstream activation of caspase 1, IL-1\316\262, and IL-18. Previous studies have shown that the interferon gamma inducible HIN-200 family member, Absent in Melanoma 2 (AIM2) is primarily responsible for recognition of F. tularensis, and there are conflicting reports about the role of NLRP3 in recognition and innate immune defenses against the bacteria. The objective of this study initially was to investigate the underappreciated role of bacterial antioxidants in cytosolic innate immune subversion. Interestingly, in the course of our investigation to elucidate the role of antioxidant enzymes of F. tularensis in suppression of the inflammasome, our results demonstrated that NLRP3 increased host susceptibility to infection. The loss of NLRP3 led to elevated transcription of aim2, enhanced activation of NF-\316\272B and MAPK signaling pathways, and elevated levels of IL-1\316\262, IL-18, and TNF-\316\261. Furthermore, NLRP3 deficiency resulted in improved clearance of F. tularensis as compared to wild type (WT) counterparts in both an in vitro and in vivo mouse model. Finally, NLRP3-/- mice infected with F. tularensis exhibit decreased severity of histopathological lesions and have an extended median survival time as compared to WT mice. Collectively, this study details the detrimental role of NLRP3 in F. tularensis pathogenesis and highlights NLRP3 as a potential target for the development of therapeutics for the treatment or prevention of tularemia.
Citation
Westcott EL. The role of NLRP3 in modulating innate immune responses against Francisella Tularensis [thesis]. Ann Arbor (MI): Proquest LLC; 2016. 96 p.
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