The abundant neutrophil protein calprotectin enhances host killing of Staphylococcus aureus by inhibiting the ability of the bacterium to respond to the neutrophil oxidative burst, according to a new publication in Cell Host & Microbe.

metal sequestration by calprotectin could be an important line of defence against many clinically relevant organisms.

To survive in a eukaryotic host, bacterial pathogens must acquire essential nutrients, including metals. In turn, the host can inhibit microbial growth by sequestering these vital cofactors. Much is known about the tussle between pathogens and their eukaryotic hosts for iron, but it is beginning to be appreciated that other transition metals such as Mn and Zn are also important.

From previous work it was known that calprotectin sequesters Mn and Zn and inhibits bacterial growth, but the bacterial processes affected were unclear. Neutrophils kill microbial pathogens in part through the release of reactive oxygen species such as superoxide, and the bacteria attempt to fend off the toxic effects of these molecules using Mn- or Zn-dependent superoxide dismutases (SODs). Thomas Kehl-Fie et al. were interested in whether the sequestration of metals by calprotectin could interfere with the response of S. aureus to superoxide stress. In an in vitro assay they found that the presence of calprotectin enhanced the susceptibility of two different S. aureus strains to superoxide and that this effect could be mitigated by the addition of excess Mn or Zn. Furthermore, the half-maximal inhibitory concentration (IC50) of a mutant calprotectin (ΔZn/Mn), in which the residues predicted to be important in Mn and Zn binding had been mutated, was 60 times that of the wild-type protein. To pinpoint the mechanism involved, Kehl-Fie et al. looked at S. aureus Mn-dependent SODs and found that their activity was reduced in the presence of calprotectin. This reduction was not observed in the ΔZn/Mn mutant, indicating that metal sequestration is required for this effect. Finally, it was shown that in mice calprotectin enhanced the susceptibility of S. aureus to neutrophil attack and that mice which were deficient in calprotectin were more susceptible to S. aureus infection.

As Mn- or Zn-dependent proteins, including SODs, are found in a range of bacterial pathogens, Kehl-Fie et al. conclude that metal sequestration by calprotectin could be an important line of defence against many clinically relevant organisms.