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 H2O2 at 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 H2O2 that still effectively kill Salmonella, but most H2O2 would 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 H2O2 release. 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 H2O2 into highly reactive, microbicidal and locally confined HOCl at pathogen surfaces.

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Figure 1: Computational model of ROS generation and leakage in neutrophil phagosomes containing Salmonella.
Figure 2: ROS generation and leakage of human neutrophils in vitro.
Figure 3: H2O2 exposure of Salmonella in spleen of wild-type and MPO-deficient mice as revealed by a Salmonella biosensor strain.
Figure 4: Collateral tissue damage in the absence of MPO.

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Acknowledgements

The authors thank K. Ullrich and R. Kühl for taking blood from human donors, and thank all donors for blood donations. The authors thank I. Bartholomaeus and A. Martin for support with confocal microscopy. This study was supported in part by grants from the Swiss National Foundation (310030_156818 to D.B., PZ00P3_142403 to N.K. and PP00P3_144863 to M.R.) and the Gebert Rüf Foundation (GRS 058/14 to C.H., A.-V.B. and M.R.).

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N.S., P.F., B.F., N.E., A.T.-P., J.L. and D.B. performed experiments and analysed the data. O.C. and D.B. wrote code and ran the computational models. A.-V.B., C.H. and M.R. recruited patients. N.S., P.F., W.-D.H., N.K. and D.B. designed experiments. N.S., P.F. and D.B. wrote the paper.

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Correspondence to Dirk Bumann.

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The authors declare no competing financial interests.

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Schürmann, N., Forrer, P., Casse, O. et al. Myeloperoxidase targets oxidative host attacks to Salmonella and prevents collateral tissue damage. Nat Microbiol 2, 16268 (2017). https://doi.org/10.1038/nmicrobiol.2016.268

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