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bioRxiv · 10.1101/2025.04.27.650861

Role of Thioredoxin Reductase (TrxB) in Oxidative Stress Response of Francisella tularensis Live Vaccine Strain

Higgs, M. G.·Ma, Z.·Centone, A.·Bakshi, C. S.·MALIK, M.
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Abstract

Francisella tularensis is an important human pathogen responsible for causing tularemia in the Northern Hemisphere. Francisella has been developed as a biological weapon in the past due to its extremely high virulence. F. tularensis is a Gram-negative, intracellular pathogen that primarily infects macrophages. To counteract the reactive oxygen and nitrogen species (ROS/RNS) produced by macrophages in response to infection, F. tularensis encodes a repertoire of antioxidant enzymes. Among these, the thioredoxin system is critical for maintaining cellular redox homeostasis by regulating the balance between oxidation and reduction within bacterial cells. This system includes thioredoxins, thioredoxin reductase, and NADPH. Despite its potential importance, the thioredoxin system of F. tularensis remains understudied. F. tularensis possesses two thioredoxin genes, trxA1 (FTL_0611) and trxA2 (FTL_1224), and a single thioredoxin reductase gene, trxB (FTL_1571). In this study, we characterized the role of trxB in oxidative stress resistance. Our findings demonstrate that trxB is essential for oxidative stress resistance in F. tularensis and that its loss increases susceptibility to several antibiotics. However, unlike in other bacterial species, TrxB in F. tularensis is not a functional target of the gold-containing antimicrobial agent auranofin. We also show that OxyR, the master regulator of oxidative stress responses, directly controls trxB expression under oxidative stress conditions. Furthermore, TrxB contributes to intramacrophage survival by enabling the bacterium to withstand ROS-induced oxidative stress. Collectively, this study highlights a critical, previously uncharacterized antioxidant defense mechanism in F. tularensis, highlighting its importance in oxidative stress resistance and intramacrophage survival.

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Higgs, M. G., Ma, Z., Centone, A., Bakshi, C. S., MALIK, M.. 2025-04-27. Role of Thioredoxin Reductase (TrxB) in Oxidative Stress Response of Francisella tularensis Live Vaccine Strain. https://doi.org/10.1101/2025.04.27.650861

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