Intracellular Redox Modulation by Francisella tularensis Perturbs the Activation of the AIM2 Inflammasome
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Issue Date
2022-05
Authors
Miller, Jacob '22
Degree
MS in Molecular Biosciences
Advisor
Malik, Meenakshi
Committee Members
Parent, Michelle
Singh, Vir
Shakerely, Nicole
Singh, Vir
Shakerely, Nicole
Journal Title
Journal ISSN
Volume Title
Abstract
Francisella tularensis (Ft) is an intracellular gram-negative bacterium and the causative agent of tularemia. Ft is considered a potential bioterror agent due to its low infectious dose, ease of dissemination, and high mortality rates, if left untreated. Previous studies from our lab have shown that Ft can evade innate immune responses via suppression of specific pro-inflammatory pathways, including the inflammasome-mediated pathways that result in diminished cytokine production, recruitment of innate immune cells, and bacterial clearance. The cytosolic sensor, absent in melanoma 2 (AIM2), senses double-stranded DNA in the cytosol of the infected cells and then assembles a multi-protein complex known as the inflammasome. The activation of inflammasome results in the secretion of IL-1\316\262 and IL-18, the key pro-inflammatory cytokines required to clear Ft infection. Studies have demonstrated that Ft suppresses the activation of AIM2 inflammasome. However, the mechanism of suppression is currently unknown. We have demonstrated that F. tularensis suppresses the AIM2 inflammasome-mediated responses by modulating the intracellular redox environment, thereby inhibiting the release of bacterial DNA and subsequent activation of AIM2 inflammasome. An Ft mutant deficient in the transcriptional regulator of oxidative stress, OxyR (\316\224oxyR), was used to address this hypothesis. The OxyR is a master regulator of key antioxidant enzymes of Ft and is also required for maintaining the redox homeostasis in infected macrophages. Our results show an elevated expression of AIM2-dependent IL-1\316\262 in macrophages infected with the \316\224oxyR mutant when compared to their wild-type counterparts. The elevated levels of IL-1\316\262 are associated with the activation of AIM2-dependent caspase-1 in the \316\224oxyR mutant infected macrophages. The expression of key signaling components upstream of the AIM2 inflammasome, are also significantly higher in macrophages infected with the \316\224oxyR mutant than their wild-type counterparts. However, these changes were reversed in the OxyR infected NADPH-oxidase deficient macrophages, which cannot generate reactive oxygen species. These results indicate that the redox environment modulated by OxyR of Ft may have a crucial role in suppressing key signaling components of the AIM2 inflammasome. Collectively, the findings from these studies will aid in extending the knowledge of how Ft-encoded factors subvert the host\342\200\231s innate immune responses.
Citation
Miller J. Intracellular redox modulation by Francisella tularensis perturbs the activation of the AIM2 inflammasome [thesis]. Ann Arbor (MI): Proquest LLC; 2022. 90 p.
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