Elucidating the role of thioredoxin in the oxidative stress response of Francisella tularensis
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Issue Date
2020-07
Authors
Higgs, Matthew '20
Degree
MS in Molecular Biosciences
Advisor
Malik, Meenakshi
Committee Members
Parent, Michelle
Shakerley, Nicole
Shakerley, Nicole
Journal Title
Journal ISSN
Volume Title
Abstract
Francisella tularensis is an important human pathogen responsible for causing a fatal human disease known as tularemia. F. tularensis is classified as a Tier 1 Category A select agent by the CDC based on its possible use as a bioterror agent. F. tularensis must survive respiratory burst once it enters the host\342\200\231s phagocytic cells. Francisella does so via a potent oxidative stress response that consists of several antioxidant enzymes such as superoxide dismutases B and C (SodB/C), catalase (KatG), and alkyl hydroperoxide reductase (AhpC) all of which have been previously characterized in F. tularensis. The purpose of this study was to investigate the unknown role of thioredoxin(s) in the oxidative stress response of F.tularensis. F. tularensis encodes two thioredoxins encoded by the trx and trx1 genes. We investigated how thioredoxins of F. tularensis contribute to the oxidative stress response and intracellular survival. We generated gene deletion mutants of the thioredoxin genes of F. tularensis. Our results demonstrate that loss of trx led to enhanced sensitivity to oxidative stress and attenuated intramacrophage growth. Loss of trx also led to downregulated expression of antioxidant enzyme genes ahpC, katG, and sodB. We proposed that thioredoxin acts in concert with other antioxidant enzymes to overcome oxidative stress.Our results demonstrate that trx regulates the expression of the global oxidative stress regulator, oxyR, which in turn results in the downregulation of ahpC, katG, and sodB genes. Collectively, the results of this study demonstrate that trx plays a regulatory role in the oxidative stress response of F. tularensis by controlling the expression of the oxyR gene.The results of this study are novel and highly significant to the field of Francisella research. We expect that the characterization of such pathogenic mechanisms will allow us to identify potential targets to develop better treatment or prophylactics to fight tularemia.
Citation
Higgs M. Elucidating the role of thioredoxin in the oxidative stress response of Francisella tularensis [thesis]. Ann Arbor (MI): Proquest LLC; 2020. 90 p.
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