A Secreted Bacterial Peptidylarginine Deiminase Can Neutralize Human Innate Immune Defenses

ABSTRACT The keystone oral pathogen Porphyromonas gingivalis is associated with severe periodontitis. Intriguingly, this bacterium is known to secrete large amounts of an enzyme that converts peptidylarginine into citrulline residues. The present study was aimed at identifying possible functions of...

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Autores principales:	Tim Stobernack, Marines du Teil Espina, Lianne M. Mulder, Laura M. Palma Medina, Dillon R. Piebenga, Giorgio Gabarrini, Xin Zhao, Koen M. J. Janssen, Jarnick Hulzebos, Elisabeth Brouwer, Thomas Sura, Dörte Becher, Arie Jan van Winkelhoff, Friedrich Götz, Andreas Otto, Johanna Westra, Jan Maarten van Dijl
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Porphyromonas gingivalis citrullination immune evasion neutrophils protein modification Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f1f572ae8f474774b61efd05b64e0915
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spelling	oai:doaj.org-article:f1f572ae8f474774b61efd05b64e09152021-11-15T15:58:21ZA Secreted Bacterial Peptidylarginine Deiminase Can Neutralize Human Innate Immune Defenses10.1128/mBio.01704-182150-7511https://doaj.org/article/f1f572ae8f474774b61efd05b64e09152018-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01704-18https://doaj.org/toc/2150-7511ABSTRACT The keystone oral pathogen Porphyromonas gingivalis is associated with severe periodontitis. Intriguingly, this bacterium is known to secrete large amounts of an enzyme that converts peptidylarginine into citrulline residues. The present study was aimed at identifying possible functions of this citrullinating enzyme, named Porphyromonas peptidylarginine deiminase (PPAD), in the periodontal environment. The results show that PPAD is detectable in the gingiva of patients with periodontitis, and that it literally neutralizes human innate immune defenses at three distinct levels, namely bacterial phagocytosis, capture in neutrophil extracellular traps (NETs), and killing by the lysozyme-derived cationic antimicrobial peptide LP9. As shown by mass spectrometry, exposure of neutrophils to PPAD-proficient bacteria reduces the levels of neutrophil proteins involved in phagocytosis and the bactericidal histone H2. Further, PPAD is shown to citrullinate the histone H3, thereby facilitating the bacterial escape from NETs. Last, PPAD is shown to citrullinate LP9, thereby restricting its antimicrobial activity. The importance of PPAD for immune evasion is corroborated in the infection model Galleria mellonella, which only possesses an innate immune system. Together, the present observations show that PPAD-catalyzed protein citrullination defuses innate immune responses in the oral cavity, and that the citrullinating enzyme of P. gingivalis represents a new type of bacterial immune evasion factor. IMPORTANCE Bacterial pathogens do not only succeed in breaking the barriers that protect humans from infection, but they also manage to evade insults from the human immune system. The importance of the present study resides in the fact that protein citrullination is shown to represent a new bacterial mechanism for immune evasion. In particular, the oral pathogen P. gingivalis employs this mechanism to defuse innate immune responses by secreting a protein-citrullinating enzyme. Of note, this finding impacts not only the global health problem of periodontitis, but it also extends to the prevalent autoimmune disease rheumatoid arthritis, which has been strongly associated with periodontitis, PPAD activity, and loss of tolerance against citrullinated proteins, such as the histone H3.Tim StobernackMarines du Teil EspinaLianne M. MulderLaura M. Palma MedinaDillon R. PiebengaGiorgio GabarriniXin ZhaoKoen M. J. JanssenJarnick HulzebosElisabeth BrouwerThomas SuraDörte BecherArie Jan van WinkelhoffFriedrich GötzAndreas OttoJohanna WestraJan Maarten van DijlAmerican Society for MicrobiologyarticlePorphyromonas gingivaliscitrullinationimmune evasionneutrophilsprotein modificationMicrobiologyQR1-502ENmBio, Vol 9, Iss 5 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Porphyromonas gingivalis citrullination immune evasion neutrophils protein modification Microbiology QR1-502
spellingShingle	Porphyromonas gingivalis citrullination immune evasion neutrophils protein modification Microbiology QR1-502 Tim Stobernack Marines du Teil Espina Lianne M. Mulder Laura M. Palma Medina Dillon R. Piebenga Giorgio Gabarrini Xin Zhao Koen M. J. Janssen Jarnick Hulzebos Elisabeth Brouwer Thomas Sura Dörte Becher Arie Jan van Winkelhoff Friedrich Götz Andreas Otto Johanna Westra Jan Maarten van Dijl A Secreted Bacterial Peptidylarginine Deiminase Can Neutralize Human Innate Immune Defenses
description	ABSTRACT The keystone oral pathogen Porphyromonas gingivalis is associated with severe periodontitis. Intriguingly, this bacterium is known to secrete large amounts of an enzyme that converts peptidylarginine into citrulline residues. The present study was aimed at identifying possible functions of this citrullinating enzyme, named Porphyromonas peptidylarginine deiminase (PPAD), in the periodontal environment. The results show that PPAD is detectable in the gingiva of patients with periodontitis, and that it literally neutralizes human innate immune defenses at three distinct levels, namely bacterial phagocytosis, capture in neutrophil extracellular traps (NETs), and killing by the lysozyme-derived cationic antimicrobial peptide LP9. As shown by mass spectrometry, exposure of neutrophils to PPAD-proficient bacteria reduces the levels of neutrophil proteins involved in phagocytosis and the bactericidal histone H2. Further, PPAD is shown to citrullinate the histone H3, thereby facilitating the bacterial escape from NETs. Last, PPAD is shown to citrullinate LP9, thereby restricting its antimicrobial activity. The importance of PPAD for immune evasion is corroborated in the infection model Galleria mellonella, which only possesses an innate immune system. Together, the present observations show that PPAD-catalyzed protein citrullination defuses innate immune responses in the oral cavity, and that the citrullinating enzyme of P. gingivalis represents a new type of bacterial immune evasion factor. IMPORTANCE Bacterial pathogens do not only succeed in breaking the barriers that protect humans from infection, but they also manage to evade insults from the human immune system. The importance of the present study resides in the fact that protein citrullination is shown to represent a new bacterial mechanism for immune evasion. In particular, the oral pathogen P. gingivalis employs this mechanism to defuse innate immune responses by secreting a protein-citrullinating enzyme. Of note, this finding impacts not only the global health problem of periodontitis, but it also extends to the prevalent autoimmune disease rheumatoid arthritis, which has been strongly associated with periodontitis, PPAD activity, and loss of tolerance against citrullinated proteins, such as the histone H3.
format	article
author	Tim Stobernack Marines du Teil Espina Lianne M. Mulder Laura M. Palma Medina Dillon R. Piebenga Giorgio Gabarrini Xin Zhao Koen M. J. Janssen Jarnick Hulzebos Elisabeth Brouwer Thomas Sura Dörte Becher Arie Jan van Winkelhoff Friedrich Götz Andreas Otto Johanna Westra Jan Maarten van Dijl
author_facet	Tim Stobernack Marines du Teil Espina Lianne M. Mulder Laura M. Palma Medina Dillon R. Piebenga Giorgio Gabarrini Xin Zhao Koen M. J. Janssen Jarnick Hulzebos Elisabeth Brouwer Thomas Sura Dörte Becher Arie Jan van Winkelhoff Friedrich Götz Andreas Otto Johanna Westra Jan Maarten van Dijl
author_sort	Tim Stobernack
title	A Secreted Bacterial Peptidylarginine Deiminase Can Neutralize Human Innate Immune Defenses
title_short	A Secreted Bacterial Peptidylarginine Deiminase Can Neutralize Human Innate Immune Defenses
title_full	A Secreted Bacterial Peptidylarginine Deiminase Can Neutralize Human Innate Immune Defenses
title_fullStr	A Secreted Bacterial Peptidylarginine Deiminase Can Neutralize Human Innate Immune Defenses
title_full_unstemmed	A Secreted Bacterial Peptidylarginine Deiminase Can Neutralize Human Innate Immune Defenses
title_sort	secreted bacterial peptidylarginine deiminase can neutralize human innate immune defenses
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/f1f572ae8f474774b61efd05b64e0915
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A Secreted Bacterial Peptidylarginine Deiminase Can Neutralize Human Innate Immune Defenses

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