Abstract
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.
Highlights
Staphylococcus aureus is a ubiquitous pathogen that colonizes 30% of the population at any given time and can infect virtually every human tissue [1]
S. aureus experiences Mn and Zn starvation during infection, yet it is still able to successfully cause infection. This fact indicates that S. aureus possesses adaptations that allow it to overcome this host defense
This screen identified a mutant that has an insertion in arlRS, which is more sensitive to CP than wild type S. aureus (Fig 1A)
Summary
Staphylococcus aureus is a ubiquitous pathogen that colonizes 30% of the population at any given time and can infect virtually every human tissue [1] These facts and the continued spread of antibiotic resistance have led both the Centers for Disease Control and the World Health Organization to state that S. aureus poses a serious threat to human health [2, 3]. Elucidating how pathogens overcome nutritional immunity, a critical component of the immune response in which the host restricts essential nutrients from the invading pathogen, has the potential to address this need Transition metals such as iron (Fe), manganese (Mn) and zinc (Zn) are essential for virtually all forms of life. Mice lacking CP have defects in metal sequestration and are more susceptible to a range of bacterial and fungal pathogens, including S. aureus, Acinetobacter baumannii, Klebsiella pneumoniae, and Candida albicans [8, 9, 16,17,18,19]
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