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Manganese detoxification by MntE is critical for resistance to oxidative stress and virulence of Staphylococcus aureus
Caroline M. Grunenwald, Jacob E. Choby, Lillian J. Juttukonda, William N. Beavers, Andy Weiss, Victor J. Torres, Eric P. Skaar
Manganese (Mn) is an essential micronutrient critical for the pathogenesis of Staphylococcus aureus, a significant cause of human morbidity and mortality. Paradoxically, excess Mn is toxic, thereforemaintaining intracellular Mn homeostasis is required for survival. Here we describe a Mn exporter in S. aureus, MntE, which is a member of the Cation Diffusion Facilitator protein family and conserved among Gram-positive pathogens. Upregulation of mntEtranscription in response to excess Mn is dependent on the presence of MntR, a transcriptional repressor of the mntABC Mn uptake system. Inactivation ofmntE or mntR leads to reduced growth in media supplemented with Mn, demonstrating MntE is required for detoxification of excess Mn. Inactivation ofmntE results in elevated levels of intracellular Mn, but reduced intracellular iron (Fe) levels, supporting the hypothesis that MntE functions as a Mn efflux pump and Mn efflux influences Fe homeostasis. Strains inactivated for mntEare more sensitive to the oxidants NaOCl and paraquat, indicating Mn homeostasis is critical for resisting oxidative stress. Furthermore, mntE and mntR are required for full virulence of S. aureusduring infection, suggesting S. aureusexperiences Mn toxicity in vivo. Combined, these data support a model where MntR controls Mn homeostasis by balancing transcriptional repression of mntABCand induction of mntE,both of which are critical for S. aureus pathogenesis. Thus, Mn efflux contributes to bacterial survival and virulence during infection, establishing MntE as a potential antimicrobial target and expanding our understanding of Mn homeostasis.