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mBio

Title:		A Secreted Bacterial Peptidylarginine Deiminase Can Neutralize Human Innate Immune Defenses
Author(s):		Stobernack T; du Teil Espina M; Mulder LM; Palma Medina LM; Piebenga DR; Gabarrini G; Zhao X; Janssen KMJ; Hulzebos J; Brouwer E; Sura T; Becher D; van Winkelhoff AJ; Gotz F; Otto A; Westra J; van Dijl JM;
Address:		"Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Department of Periodontology, University of Groningen, University Medical Center Groningen, Center for Dentistry and Oral Hygiene, Groningen, The Netherlands. Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Institute for Microbiology, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. Microbial Genetics, Interfaculty Institute of Microbiology and Infection Medicine and Infection Medicine (IMIT), University of Tubingen, Tubingen, Germany. Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands j.m.van.dijl01@umcg.nl"
Journal Title:		mBio
Year:		2018
Volume:		20181030
Issue:		5
Page Number:		-
DOI:		10.1128/mBio.01704-18
ISSN/ISBN:		2150-7511 (Electronic)
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"
Keywords:		"Adult Antimicrobial Cationic Peptides/antagonists & inhibitors Extracellular Traps/drug effects Female Gingiva/chemistry/microbiology Humans *Immune Evasion Immunity, Innate/*drug effects Male Periodontitis/*microbiology/pathology Phagocytosis/drug effect;"
Notes:		"MedlineStobernack, Tim du Teil Espina, Marines Mulder, Lianne M Palma Medina, Laura M Piebenga, Dillon R Gabarrini, Giorgio Zhao, Xin Janssen, Koen M J Hulzebos, Jarnick Brouwer, Elisabeth Sura, Thomas Becher, Dorte van Winkelhoff, Arie Jan Gotz, Friedrich Otto, Andreas Westra, Johanna van Dijl, Jan Maarten eng Research Support, Non-U.S. Gov't 2018/11/01 mBio. 2018 Oct 30; 9(5):e01704-18. doi: 10.1128/mBio.01704-18"