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

What was studied?

This study focused on how Staphylococcus aureus adapts to host-imposed manganese (Mn) and zinc (Zn) starvation, particularly in the presence of the host immune effector, calprotectin (CP), which binds these metals. The research identified the role of the two-component system ArlRS in enabling S. aureus to resist CP-induced Mn starvation by modulating bacterial metabolism and metal acquisition.

Who was studied?

The study primarily examined Staphylococcus aureus, using both wild-type strains and mutant strains lacking the ArlRS system. It also investigated the effects of CP on these strains, particularly focusing on how the loss of ArlRS affects the bacterium’s ability to grow under conditions of Mn starvation during infection in both normal and CP-deficient mice.

What were the most important findings?

The study revealed that ArlRS, a global regulator in S. aureus, is crucial for the bacterium’s ability to resist host-imposed Mn starvation during infection. ArlRS modulates the bacterium’s metabolism, particularly by enhancing amino acid utilization, which reduces the need for manganese. This adaptation is especially evident when glucose, the preferred carbon source for S. aureus, is limited. Mutants lacking ArlRS were more sensitive to CP, which sequesters Mn and Zn, suggesting that ArlRS is necessary for S. aureus to adapt its metabolism in response to metal starvation. The research also showed that the ability of S. aureus to grow using amino acids, which bypasses some Mn-dependent steps in glycolysis, is disrupted when ArlRS is absent. In infection models, S. aureus strains lacking ArlRS had reduced virulence, particularly when Mn was limited, and showed decreased bacterial burdens in tissues compared to wild-type strains. These findings underscore the importance of metabolic plasticity in bacterial pathogenesis, particularly in overcoming host-imposed nutrient restrictions.

What are the greatest implications of this study?

The study highlights the role of metabolic adaptation in bacterial resistance to nutritional immunity, particularly during manganese limitation. By identifying ArlRS as a key regulator in this process, the research opens new avenues for targeting bacterial metabolism as a therapeutic strategy. Disrupting ArlRS or its regulated metabolic pathways could weaken S. aureus, making it more susceptible to the host immune response. Furthermore, understanding how S. aureus shifts from glucose to amino acid metabolism to conserve Mn could inform broader strategies to combat bacterial infections, particularly those caused by pathogens that are resistant to conventional antibiotics.