title: Myeloperoxidase targets oxidative host attacks to Salmonella and prevents collateral tissue damage.
abstract: Host control of infections crucially depends on the capability to kill pathogens with reactive oxygen species (ROS). However, these toxic molecules can also readily damage host components and cause severe immunopathology. Here, we show that neutrophils use their most abundant granule protein, myeloperoxidase, to target ROS specifically to pathogens while minimizing collateral tissue damage. A computational model predicted that myeloperoxidase efficiently scavenges diffusible H2O2at the surface of phagosomal Salmonella and converts it into highly reactive HOCl (bleach), which rapidly damages biomolecules within a radius of less than 0.1 μm. Myeloperoxidase-deficient neutrophils were predicted to accumulate large quantities of H2O2that still effectively kill Salmonella, but most H2O2would leak from the phagosome. Salmonella stimulation of neutrophils from normal and myeloperoxidase-deficient human donors experimentally confirmed an inverse relationship between myeloperoxidase activity and extracellular H2O2release. Myeloperoxidase-deficient mice infected with Salmonella had elevated hydrogen peroxide tissue levels and exacerbated oxidative damage of host lipids and DNA, despite almost normal Salmonella control. These data show that myeloperoxidase has a major function in mitigating collateral tissue damage during antimicrobial oxidative bursts, by converting diffusible long-lived H2O2into highly reactive, microbicidal and locally confined HOCl at pathogen surfaces.
authors.affiliation: Focal Area Infection Biology, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Nura
authors.initials: N
authors.lastname: Schürmann
authors.affiliation: Department Biomedicine and University Hospital Basel, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Forrer
authors.affiliation: Focal Area Infection Biology, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Casse
authors.affiliation: Focal Area Infection Biology, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Jiagui
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Microbiology, ETH Zurich, CH-8093 Zurich, Switzerland.
authors.forename: Boas
authors.initials: B
authors.lastname: Felmy
authors.affiliation: Department Biomedicine and University Hospital Basel, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Anne-Valérie
authors.initials: AV
authors.lastname: Burgener
authors.affiliation: Imaging Core Facility, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Ehrenfeuchter
authors.affiliation: Institute of Microbiology, ETH Zurich, CH-8093 Zurich, Switzerland.
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Hardt
authors.affiliation: Department Biomedicine and University Hospital Basel, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Mike
authors.initials: M
authors.lastname: Recher
authors.affiliation: Department Biomedicine and University Hospital Basel, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hess
authors.affiliation: Department Biomedicine and University Hospital Basel, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Astrid
authors.initials: A
authors.lastname: Tschan-Plessl
authors.affiliation: Department Biomedicine and University Hospital Basel, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Nina
authors.initials: N
authors.lastname: Khanna
authors.affiliation: Focal Area Infection Biology, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bumann
mesh_terms: D000818:Animals; D003198:Computer Simulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006997:Hypochlorous Acid / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism / Q000382:microbiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst; D012475:Salmonella / Q000378:metabolism* / Q000472:pathogenicity
chemical_list: D017382:Reactive Oxygen Species; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D009195:Peroxidase