MntABC and MntH Enable Staphylococcus aureus to Overcome Host Nutritional Immunity and Manganese Starvation Original paper

What was studied?

This study investigated the roles of two manganese transport systems in Staphylococcus aureus—MntABC (an ATP-binding cassette transporter) and MntH (a NRAMP family transporter)—in enabling the bacterium to overcome manganese starvation imposed by the host protein calprotectin. Calprotectin, an antimicrobial protein released by neutrophils, sequesters manganese and zinc during infection as part of a broader nutritional immunity strategy. The researchers explored how MntABC and MntH allow S. aureus to retain manganese-dependent superoxide dismutase (SOD) activity and persist in systemic infection despite calprotectin-mediated metal withholding.

Who was studied?

The study utilized both wild-type and genetically modified S. aureus strains (mntC, mntH, and double mutants), tested in vitro and in vivo. Murine models included wild-type C57BL/6 mice and S100A9 knockout mice, which lack calprotectin. These models allowed the authors to assess bacterial burdens, metal distribution, and protein expression across different organs, particularly the liver and kidneys, during systemic infection.

Most important findings

The expression of both mntA (MntABC) and mntH increased in response to calprotectin exposure, indicating a manganese-specific starvation response. Double mutants lacking both MntABC and MntH showed significantly impaired growth in manganese-limited environments and had markedly reduced SOD activity, resulting in elevated oxidative stress. In wild-type mice, the double mutants demonstrated significantly reduced bacterial burdens in liver and kidneys, confirming their impaired virulence. However, in calprotectin-deficient mice, these defects were largely rescued in the liver, confirming calprotectin as the primary manganese-sequestering factor there.

Importantly, the study used engineered calprotectin variants to demonstrate that the loss of virulence in double mutants was due to manganese, not zinc, starvation. Moreover, LA-ICP-MS imaging showed that while manganese levels are inherently lower in the kidney than in the liver, infection further restricts local manganese and zinc concentrations—yet this restriction in kidneys occurred even without calprotectin, suggesting additional, CP-independent mechanisms of manganese sequestration.

Key implications

This study emphasizes manganese as a critical nutrient that S. aureus must acquire during infection, highlighting the importance of microbial transport systems in overcoming nutritional immunity. The finding that manganese availability, not zinc, is the primary factor limiting S. aureus persistence underlines manganese sequestration as a potential therapeutic target. Moreover, the discovery of calprotectin-independent manganese restriction in the kidney suggests the existence of redundant or parallel host mechanisms to limit metal availability, pointing to underexplored targets in innate immunity. These insights underscore the role of manganese homeostasis in shaping microbial pathogenesis and the host’s metal-withholding defense network.