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During infection the host imposes manganese and zinc starvation on invading pathogens. Despite this,  Staphylococcus aureus  and other successful pathogens remain capable of causing devastating disease. However, how these invaders adapt to host-imposed metal starvation and overcome nutritional immunity remains unknown. We report that ArlRS, a global staphylococcal virulence regulator, enhances the ability of  S .  aureus  to grow in the presence of the manganese-and zinc-binding innate immune effector calprotectin. Utilization of calprotectin variants with altered metal binding properties revealed that strains lacking ArlRS are specifically more sensitive to manganese starvation. Loss of ArlRS did not alter the expression of manganese importers or prevent  S .  aureus  from acquiring metals. It did, however, alter staphylococcal metabolism and impair the ability of  S .  aureus  to grow on amino acids. Further studies suggested that relative to consuming glucose, the preferred carbon source of  S .  aureus , utilizing amino acids reduced the cellular demand for manganese. When forced to use glucose as the sole carbon source  S .  aureus  became more sensitive to calprotectin compared to when amino acids are provided. Infection experiments utilizing wild type and calprotectin-deficient mice, which have defects in manganese sequestration, revealed that ArlRS is important for disease when manganese availability is restricted but not when this essential nutrient is freely available. In total, these results indicate that altering cellular metabolism contributes to the ability of pathogens to resist manganese starvation and that ArlRS enables  S .  aureus  to overcome nutritional immunity by facilitating this adaptation.

The Two-Component System ArlRS and Alterations in Metabolism Enable Staphylococcus aureus to Resist Calprotectin-Induced Manganese Starvation