Mycoredoxins Are Required for Redox Homeostasis and Intracellular Survival in the Actinobacterial Pathogen .

is a facultative intracellular pathogen that can survive within macrophages of a wide variety of hosts, including immunosuppressed humans. Current antibiotherapy is often ineffective, and novel therapeutic strategies are urgently needed to tackle infections caused by this pathogen. In this study, we identified three mycoredoxin-encoding genes () in the genome of , and we investigated their role in virulence. Importantly, the intracellular survival of a triple -null mutant () in murine macrophages was fully impaired. However, each mycoredoxin alone could restore the intracellular proliferation rate of to wild type levels, suggesting that these proteins could have overlapping functions during host cell infection. Experiments with the reduction-oxidation sensitive green fluorescent protein 2 (roGFP2) biosensor confirmed that was exposed to redox stress during phagocytosis, and mycoredoxins were involved in preserving the redox homeostasis of the pathogen. Thus, we studied the importance of each mycoredoxin for the resistance of to different oxidative stressors. Interestingly, all genes did have overlapping roles in the resistance to sodium hypochlorite. In contrast, only was essential for the survival against high concentrations of nitric oxide, while was not required for the resistance to hydrogen peroxide. Our results suggest that all mycoredoxins have important roles in redox homeostasis, contributing to the pathogenesis of and, therefore, these proteins may be considered interesting targets for the development of new anti-infectives.