Immune evasion by a staphylococcal inhibitor of myeloperoxidase

Nienke W.M. De Jong, Kasra X. Ramyar, Fermin E. Guerra, Reindert Nijland, Cindy Fevre, Jovanka M. Voyich, Alex J. McCarthy, Brandon L. Garcia, Kok P.M. Van Kessel, Jos A.G. van Strijp, Brian V. Geisbrecht, Pieter Jan A. Haas

Research output: Contribution to journalArticleAcademicpeer-review

19 Citations (Scopus)

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 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. Moreover, 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.
LanguageEnglish
Pages9439-9444
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number35
DOIs
Publication statusPublished - 2017

Fingerprint

Immune Evasion
Peroxidase
Neutrophils
Staphylococcus aureus
Phagocytosis
Bacteria
Phagosomes
Survival
Bacteriophages

Keywords

  • Immune evasion
  • Myeloperoxidase
  • Neutrophil
  • Phagocytosis
  • Staphylococcus aureus

Cite this

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. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 35. pp. 9439-9444.
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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-{\AA} 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. Moreover, 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.",
keywords = "Immune evasion, Myeloperoxidase, Neutrophil, Phagocytosis, Staphylococcus aureus",
author = "{De Jong}, {Nienke W.M.} and Ramyar, {Kasra X.} and Guerra, {Fermin E.} and Reindert Nijland and Cindy Fevre 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.}",
year = "2017",
doi = "10.1073/pnas.1707032114",
language = "English",
volume = "114",
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De Jong, NWM, Ramyar, KX, Guerra, FE, Nijland, R, Fevre, C, Voyich, JM, McCarthy, AJ, Garcia, BL, Van Kessel, KPM, van Strijp, JAG, Geisbrecht, BV & Haas, PJA 2017, 'Immune evasion by a staphylococcal inhibitor of myeloperoxidase', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 35, pp. 9439-9444. https://doi.org/10.1073/pnas.1707032114

Immune evasion by a staphylococcal inhibitor of myeloperoxidase. / 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.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 35, 2017, p. 9439-9444.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Immune evasion by a staphylococcal inhibitor of myeloperoxidase

AU - De Jong, Nienke W.M.

AU - Ramyar, Kasra X.

AU - Guerra, Fermin E.

AU - Nijland, Reindert

AU - Fevre, Cindy

AU - Voyich, Jovanka M.

AU - McCarthy, Alex J.

AU - Garcia, Brandon L.

AU - Van Kessel, Kok P.M.

AU - van Strijp, Jos A.G.

AU - Geisbrecht, Brian V.

AU - Haas, Pieter Jan A.

PY - 2017

Y1 - 2017

N2 - 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. Moreover, 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.

AB - 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. Moreover, 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.

KW - Immune evasion

KW - Myeloperoxidase

KW - Neutrophil

KW - Phagocytosis

KW - Staphylococcus aureus

U2 - 10.1073/pnas.1707032114

DO - 10.1073/pnas.1707032114

M3 - Article

VL - 114

SP - 9439

EP - 9444

JO - Proceedings of the National Academy of Sciences of the United States of America

T2 - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 35

ER -