posted on 2024-01-23, 20:20authored byJanet
J. Y. Peet, Angelica D. Phan, Amanda G. Oglesby, Elizabeth M. Nolan
Pathogen
sensing by the mammalian host induces a pro-inflammatory
response that involves release of the antimicrobial metal-sequestering
protein calprotectin (CP, S100A8/S100A9 heterooligomer, MRP8/MRP14
heterooligomer) from neutrophils. Biochemical investigations on human
CP (hCP) have informed the molecular basis of how this protein sequesters
metal ions. Murine models of infection have provided invaluable insights
into the ability of murine CP (mCP) to compete with bacterial pathogens
for essential metal nutrients. Despite this extensive work, our knowledge
of how mCP sequesters metals from bacterial pathogens and its impacts
on bacterial physiology is limited. Moreover, whether mCP sequesters
iron and induces iron-starvation responses in bacterial pathogens
has not been evaluated. Here, we examine the ability of mCP to withhold
iron from Pseudomonas aeruginosa, a
Gram-negative opportunistic pathogen that causes severe infections
in immunocompromised individuals and cystic fibrosis patients. We
demonstrate that mCP prevents iron uptake and induces iron-starvation
responses in P. aeruginosa laboratory
strains PA14 and PAO1 and the JSRI-1 clinical isolate from a cystic
fibrosis patient. We also show that mCP prevents iron uptake and induces
an iron-starvation response in the Gram-positive bacterial pathogen Staphylococcus aureus. The His6 site of
mCP is the iron-sequestering site; it exhibits Ca(II)-dependent Fe(II)
affinity and binds Fe(II) with subpicomolar affinity in the presence
of excess Ca(II) ions. This work is important for understanding the
structure, function, and physiological consequences of mCP and how
the mammalian host and bacterial pathogens compete for essential metal
nutrients.