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.

doi:10.1073/pnas.1707032114

Title: Immune evasion by a staphylococcal inhibitor of myeloperoxidase

Journal Article · Mon Aug 14 00:00:00 EDT 2017 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1707032114· OSTI ID:1408117

de Jong, Nienke W. M. ^[1]; Ramyar, Kasra X. ^[2]; Guerra, Fermin E. ^[3];

^[4]; Fevre, Cindy ^[1]; Voyich, Jovanka M. ^[3]; McCarthy, Alex J. ^[1]; Garcia, Brandon L. ^[2]; van Kessel, Kok P. M. ^[1]; van Strijp, Jos A. G. ^[1]; Geisbrecht, Brian V. ^[2]; Haas, Pieter-Jan A. ^[1]

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)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); ZonMw Grant

Grant/Contract Number:: W-31-109-Eng-38; AI111203; GM121511; R01AI1090046; PAR98-072; RR020185; 205200004

OSTI ID:: 1408117

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, Issue 35; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 58 works

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59 BASIC BIOLOGICAL SCIENCES
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Title: Immune evasion by a staphylococcal inhibitor of myeloperoxidase

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