title: Nutrient metal sequestration by calprotectin inhibits bacterial superoxide defense, enhancing neutrophil killing of Staphylococcus aureus.
abstract: By sequestering manganese and zinc, the neutrophil protein calprotectin plays a crucial role in host defense against bacterial and fungal pathogens. However, the essential processes disrupted by calprotectin remain unknown. We report that calprotectin enhances the sensitivity of Staphylococcus aureus to superoxide through inhibition of manganese-dependent bacterial superoxide defenses, thereby increasing superoxide levels within the bacterial cell. Superoxide dismutase activity is required for full virulence in a systemic model of S. aureus infection, and disruption of staphylococcal superoxide defenses by calprotectin augments the antimicrobial activity of neutrophils promoting in vivo clearance. Calprotectin mutated in two transition metal binding sites and therefore defective in binding manganese and zinc does not inhibit microbial growth, unequivocally linking the antimicrobial properties of calprotectin to metal chelation. These results suggest that calprotectin contributes to host defense by rendering bacterial pathogens more sensitive to host immune effectors and reducing bacterial growth.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Kehl-Fie
authors.forename: Seth
authors.initials: S
authors.lastname: Chitayat
authors.forename: M Indriati
authors.initials: MI
authors.lastname: Hood
authors.forename: Steven
authors.initials: S
authors.lastname: Damo
authors.forename: Nicole
authors.initials: N
authors.lastname: Restrepo
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia
authors.forename: Kim A
authors.initials: KA
authors.lastname: Munro
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Chazin
authors.forename: Eric P
authors.initials: EP
authors.lastname: Skaar
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000276:immunology; D004195:Disease Models, Animal; D039841:Leukocyte L1 Antigen Complex / Q000276:immunology*; D008297:Male; D008345:Manganese / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology*; D018384:Oxidative Stress; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000276:immunology; D013482:Superoxide Dismutase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D039841:Leukocyte L1 Antigen Complex; D013481:Superoxides; D008345:Manganese; D013482:Superoxide Dismutase; D015032:Zinc