skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Immune evasion by a staphylococcal inhibitor of myeloperoxidase

Abstract

Staphylococcus aureus is highly adapted to its host and has evolved many strategies to resist opsonization and phagocytosis. Even after uptake by neutrophils, S. aureus shows resistance to killing, which suggests the presence of phagosomal immune evasion molecules. With the aid of secretome phage display, we identified a highly conserved protein that specifically binds and inhibits human myeloperoxidase (MPO), a major player in the oxidative defense of neutrophils. We have named this protein “staphylococcal peroxidase inhibitor” (SPIN). To gain insight into inhibition of MPO by SPIN, we solved the cocrystal structure of SPIN bound to a recombinant form of human MPO at 2.4-Å resolution. This structure reveals that SPIN acts as a molecular plug that prevents H 2O 2 substrate access to the MPO active site. In subsequent experiments, we observed that SPIN expression increases inside the neutrophil phagosome, where MPO is located, compared with outside the neutrophil. Furthermore, bacteria with a deleted gene encoding SPIN showed decreased survival compared with WT bacteria after phagocytosis by neutrophils. Taken together, our results demonstrate that S. aureus secretes a unique proteinaceous MPO inhibitor to enhance survival by interfering with MPO-mediated killing.

Authors:
 [1];  [2];  [3]; ORCiD logo [4];  [1];  [3];  [1];  [2];  [1];  [1];  [2];  [1]
  1. Univ. Medical Center Utrecht (The Netherlands)
  2. Kansas State Univ., Manhattan, KS (United States)
  3. Montana State Univ., Bozeman, MT (United States)
  4. Univ. Medical Center Utrecht (The Netherlands); Wageningen Univ. (The Netherlands)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH); ZonMw Grant
OSTI Identifier:
1408117
Grant/Contract Number:  
W-31-109-Eng-38; AI111203; GM121511; R01AI1090046; PAR98-072; RR020185; 205200004
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 114; Journal Issue: 35; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; immune; evasion; myeloperoxidase; neutrophil; phagocytosis; Staphylococcus aureus

Citation Formats

de Jong, Nienke W. M., Ramyar, Kasra X., Guerra, Fermin E., Nijland, Reindert, Fevre, Cindy, Voyich, Jovanka M., McCarthy, Alex J., Garcia, Brandon L., van Kessel, Kok P. M., van Strijp, Jos A. G., Geisbrecht, Brian V., and Haas, Pieter-Jan A. Immune evasion by a staphylococcal inhibitor of myeloperoxidase. United States: N. p., 2017. Web. doi:10.1073/pnas.1707032114.
de Jong, Nienke W. M., Ramyar, Kasra X., Guerra, Fermin E., Nijland, Reindert, Fevre, Cindy, Voyich, Jovanka M., McCarthy, Alex J., Garcia, Brandon L., van Kessel, Kok P. M., van Strijp, Jos A. G., Geisbrecht, Brian V., & Haas, Pieter-Jan A. Immune evasion by a staphylococcal inhibitor of myeloperoxidase. United States. doi:10.1073/pnas.1707032114.
de Jong, Nienke W. M., Ramyar, Kasra X., Guerra, Fermin E., Nijland, Reindert, Fevre, Cindy, Voyich, Jovanka M., McCarthy, Alex J., Garcia, Brandon L., van Kessel, Kok P. M., van Strijp, Jos A. G., Geisbrecht, Brian V., and Haas, Pieter-Jan A. Mon . "Immune evasion by a staphylococcal inhibitor of myeloperoxidase". United States. doi:10.1073/pnas.1707032114. https://www.osti.gov/servlets/purl/1408117.
@article{osti_1408117,
title = {Immune evasion by a staphylococcal inhibitor of myeloperoxidase},
author = {de Jong, Nienke W. M. and Ramyar, Kasra X. and Guerra, Fermin E. and Nijland, Reindert and Fevre, Cindy and Voyich, Jovanka M. and McCarthy, Alex J. and Garcia, Brandon L. and van Kessel, Kok P. M. and van Strijp, Jos A. G. and Geisbrecht, Brian V. and Haas, Pieter-Jan A.},
abstractNote = {Staphylococcus aureus is highly adapted to its host and has evolved many strategies to resist opsonization and phagocytosis. Even after uptake by neutrophils, S. aureus shows resistance to killing, which suggests the presence of phagosomal immune evasion molecules. With the aid of secretome phage display, we identified a highly conserved protein that specifically binds and inhibits human myeloperoxidase (MPO), a major player in the oxidative defense of neutrophils. We have named this protein “staphylococcal peroxidase inhibitor” (SPIN). To gain insight into inhibition of MPO by SPIN, we solved the cocrystal structure of SPIN bound to a recombinant form of human MPO at 2.4-Å resolution. This structure reveals that SPIN acts as a molecular plug that prevents H2O2 substrate access to the MPO active site. In subsequent experiments, we observed that SPIN expression increases inside the neutrophil phagosome, where MPO is located, compared with outside the neutrophil. Furthermore, bacteria with a deleted gene encoding SPIN showed decreased survival compared with WT bacteria after phagocytosis by neutrophils. Taken together, our results demonstrate that S. aureus secretes a unique proteinaceous MPO inhibitor to enhance survival by interfering with MPO-mediated killing.},
doi = {10.1073/pnas.1707032114},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {0027-8424},
number = 35,
volume = 114,
place = {United States},
year = {2017},
month = {8}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 18 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

X-ray Crystal Structure and Characterization of Halide-binding Sites of Human Myeloperoxidase at 1.8 Å Resolution
journal, April 2000

  • Fiedler, Tristan J.; Davey, Curt A.; Fenna, Roger E.
  • Journal of Biological Chemistry, Vol. 275, Issue 16
  • DOI: 10.1074/jbc.275.16.11964

Secrets of the secretome in Staphylococcus aureus
journal, March 2014

  • Kusch, Harald; Engelmann, Susanne
  • International Journal of Medical Microbiology, Vol. 304, Issue 2
  • DOI: 10.1016/j.ijmm.2013.11.005

Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity
journal, July 2005

  • Liu, George Y.; Essex, Anthony; Buchanan, John T.
  • The Journal of Experimental Medicine, Vol. 202, Issue 2
  • DOI: 10.1084/jem.20050846

Binding and inhibition of myeloperoxidase (MPO): a major function of ceruloplasmin?
journal, April 1997


Neutrophil NET formation is regulated from the inside by myeloperoxidase-processed reactive oxygen species
journal, December 2015


In vitro antibacterial activity of E-101 Solution, a novel myeloperoxidase-mediated antimicrobial, against Gram-positive and Gram-negative pathogens
journal, November 2010

  • Denys, G. A.; Grover, P.; O'Hanley, P.
  • Journal of Antimicrobial Chemotherapy, Vol. 66, Issue 2
  • DOI: 10.1093/jac/dkq429

Staphylococcus aureus innate immune evasion is lineage-specific: A bioinfomatics study
journal, October 2013


Ceruloplasmin Is an Endogenous Inhibitor of Myeloperoxidase
journal, January 2013

  • Chapman, Anna L. P.; Mocatta, Tessa J.; Shiva, Sruti
  • Journal of Biological Chemistry, Vol. 288, Issue 9
  • DOI: 10.1074/jbc.M112.418970

Genetic Tools To Enhance the Study of Gene Function and Regulation in Staphylococcus aureus
journal, January 2013

  • Bose, Jeffrey L.; Fey, Paul D.; Bayles, Kenneth W.
  • Applied and Environmental Microbiology, Vol. 79, Issue 7
  • DOI: 10.1128/AEM.00136-13

Neutrophils in innate host defense against Staphylococcus aureus infections
journal, November 2011


A human monoclonal antibody targeting the conserved staphylococcal antigen IsaA protects mice against Staphylococcus aureus bacteremia
journal, January 2015

  • van den Berg, Sanne; Bonarius, Hendrik P. J.; van Kessel, Kok P. M.
  • International Journal of Medical Microbiology, Vol. 305, Issue 1
  • DOI: 10.1016/j.ijmm.2014.11.002

Neutrophil granules and secretory vesicles in inflammation
journal, November 2003


Features and development of Coot
journal, March 2010

  • Emsley, P.; Lohkamp, B.; Scott, W. G.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
  • DOI: 10.1107/S0907444910007493

Staphylococcus aureus secretes a unique class of neutrophil serine protease inhibitors
journal, August 2014

  • Stapels, D. A. C.; Ramyar, K. X.; Bischoff, M.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 36
  • DOI: 10.1073/pnas.1407616111

Ceruloplasmin: Macromolecular Assemblies with Iron-Containing Acute Phase Proteins
journal, July 2013


The SaeR/S Gene Regulatory System Is Essential for Innate Immune Evasion by Staphylococcus aureus
journal, June 2009

  • Voyich, Jovanka M.; Vuong, Cuong; DeWald, Mark
  • The Journal of Infectious Diseases, Vol. 199, Issue 11
  • DOI: 10.1086/598967

Anti-Staphylococcal Humoral Immune Response in Persistent Nasal Carriers and Noncarriers of Staphylococcus aureus
journal, March 2009

  • Verkaik, Nelianne J.; de Vogel, Corné P.; Boelens, Hélène A.
  • Journal of Infectious Diseases, Vol. 199, Issue 5
  • DOI: 10.1086/596743

SaeR Binds a Consensus Sequence within Virulence Gene Promoters to Advance USA300 Pathogenesis
journal, January 2010

  • Nygaard, Tyler K.; Pallister, Kyler B.; Ruzevich, Peter
  • The Journal of Infectious Diseases, Vol. 201, Issue 2
  • DOI: 10.1086/649570

Chemotaxis Inhibitory Protein of Staphylococcus aureus, a Bacterial Antiinflammatory Agent
journal, March 2004

  • de Haas, Carla J. C.; Veldkamp, Karin Ellen; Peschel, Andreas
  • Journal of Experimental Medicine, Vol. 199, Issue 5
  • DOI: 10.1084/jem.20031636

Are bloodstream leukocytes Trojan Horses for the metastasis of Staphylococcus aureus?
journal, February 2011

  • Thwaites, Guy E.; Gant, Vanya
  • Nature Reviews Microbiology, Vol. 9, Issue 3
  • DOI: 10.1038/nrmicro2508

Staphylococcal superantigen-like 5 binds PSGL-1 and inhibits P-selectin–mediated neutrophil rolling
journal, November 2006


Molecular mechanisms of complement evasion: learning from staphylococci and meningococci
journal, June 2010

  • Serruto, Davide; Rappuoli, Rino; Scarselli, Maria
  • Nature Reviews Microbiology, Vol. 8, Issue 6
  • DOI: 10.1038/nrmicro2366

Ceruloplasmin has two nearly identical sites that bind myeloperoxidase
journal, October 2014

  • Bakhautdin, Bakytzhan; Goksoy Bakhautdin, Esen; Fox, Paul L.
  • Biochemical and Biophysical Research Communications, Vol. 453, Issue 4
  • DOI: 10.1016/j.bbrc.2014.09.134

Neutrophils Versus Staphylococcus aureus : A Biological Tug of War
journal, September 2013


NMRPipe: A multidimensional spectral processing system based on UNIX pipes
journal, November 1995

  • Delaglio, Frank; Grzesiek, Stephan; Vuister, GeertenW.
  • Journal of Biomolecular NMR, Vol. 6, Issue 3
  • DOI: 10.1007/BF00197809

Staphylococcus aureus Infections
journal, August 1998


ACT: the Artemis comparison tool
journal, June 2005


Myeloperoxidase: a front-line defender against phagocytosed microorganisms
journal, October 2012

  • Klebanoff, S. J.; Kettle, A. J.; Rosen, H.
  • Journal of Leukocyte Biology, Vol. 93, Issue 2
  • DOI: 10.1189/jlb.0712349

agr-Dependent Interactions of Staphylococcus aureus USA300 with Human Polymorphonuclear Neutrophils
journal, January 2010

  • Pang, Yun Yun; Schwartz, Jamie; Thoendel, Matthew
  • Journal of Innate Immunity, Vol. 2, Issue 6
  • DOI: 10.1159/000319855

Neutrophil Microbicides Induce a Pathogen Survival Response in Community-Associated Methicillin-Resistant Staphylococcus aureus
journal, December 2007

  • Palazzolo-Ballance, Amy M.; Reniere, Michelle L.; Braughton, Kevin R.
  • The Journal of Immunology, Vol. 180, Issue 1
  • DOI: 10.4049/jimmunol.180.1.500

Bovine Staphylococcus aureus Secretes the Leukocidin LukMF′ To Kill Migrating Neutrophils through CCR1
journal, June 2015


The Neutrophil NADPH Oxidase
journal, January 2002

  • Babior, B. M.; Lambeth, J. D.; Nauseef, W.
  • Archives of Biochemistry and Biophysics, Vol. 397, Issue 2
  • DOI: 10.1006/abbi.2001.2642

Insights into Mechanisms Used by Staphylococcus aureus to Avoid Destruction by Human Neutrophils
journal, September 2005

  • Voyich, Jovanka M.; Braughton, Kevin R.; Sturdevant, Daniel E.
  • The Journal of Immunology, Vol. 175, Issue 6
  • DOI: 10.4049/jimmunol.175.6.3907

Joint X-ray and neutron refinement with phenix.refine
journal, October 2010

  • Afonine, Pavel V.; Mustyakimov, Marat; Grosse-Kunstleve, Ralf W.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 11
  • DOI: 10.1107/S0907444910026582

Inference of Macromolecular Assemblies from Crystalline State
journal, September 2007


Anti-opsonic properties of staphylokinase
journal, March 2005


Myeloperoxidase: a key regulator of neutrophil oxidant production
journal, February 1997


Jalview Version 2--a multiple sequence alignment editor and analysis workbench
journal, January 2009


Staphylococcus aureus SaeR/S-regulated factors reduce human neutrophil reactive oxygen species production
journal, June 2016

  • Guerra, Fermin E.; Addison, Conrad B.; de Jong, Nienke W. M.
  • Journal of Leukocyte Biology, Vol. 100, Issue 5
  • DOI: 10.1189/jlb.4VMAB0316-100RR