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 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.
- Authors:
-
[4];
- Univ. Medical Center Utrecht (The Netherlands)
- Kansas State Univ., Manhattan, KS (United States)
- Montana State Univ., Bozeman, MT (United States)
- Univ. Medical Center Utrecht (The Netherlands); Wageningen Univ. (The Netherlands)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); 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:
- 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. https://doi.org/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. https://doi.org/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},
number = 35,
volume = 114,
place = {United States},
year = {Mon Aug 14 00:00:00 EDT 2017},
month = {Mon Aug 14 00:00:00 EDT 2017}
}
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