TY - JOUR

T1 - A Metalloproteinase Mirolysin of Tannerella forsythia Inhibits All Pathways of the Complement System

AU - Jusko, Monika

AU - Potempa, Jan

AU - Mizgalska, Danuta

AU - Bielecka, Ewa

AU - Ksiazek, Miroslaw

AU - Riesbeck, Kristian

AU - Garred, Peter

AU - Eick, Sigrun

AU - Blom, Anna M

N1 - Copyright © 2015 by The American Association of Immunologists, Inc.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Recent reports focusing on virulence factors of periodontal pathogens implicated proteinases as major determinants of remarkable pathogenicity of these species, with special emphasis on their capacity to modulate complement activity. In particular, bacteria-mediated cleavage of C5 and subsequent release of C5a seems to be an important phenomenon in the manipulation of the local inflammatory response in periodontitis. In this study, we present mirolysin, a novel metalloproteinase secreted by Tannerella forsythia, a well-recognized pathogen strongly associated with periodontitis. Mirolysin exhibited a strong effect on all complement pathways. It inhibited the classical and lectin complement pathways due to efficient degradation of mannose-binding lectin, ficolin-2, ficolin-3, and C4, whereas inhibition of the alternative pathway was caused by degradation of C5. This specificity toward complement largely resembled the activity of a previously characterized metalloproteinase of T. forsythia, karilysin. Interestingly, mirolysin released the biologically active C5a peptide in human plasma and induced migration of neutrophils. Importantly, we demonstrated that combination of mirolysin with karilysin, as well as a cysteine proteinase of another periodontal pathogen, Prevotella intermedia, resulted in a strong synergistic effect on complement. Furthermore, mutant strains of T. forsythia, devoid of either mirolysin or karilysin, showed diminished survival in human serum, providing further evidence for the synergistic inactivation of complement by these metalloproteinases. Taken together, our findings on interactions of mirolysin with complement significantly add to the understanding of immune evasion strategies of T. forsythia and expand the knowledge on molecular mechanisms driving pathogenic events in the infected periodontium.

AB - Recent reports focusing on virulence factors of periodontal pathogens implicated proteinases as major determinants of remarkable pathogenicity of these species, with special emphasis on their capacity to modulate complement activity. In particular, bacteria-mediated cleavage of C5 and subsequent release of C5a seems to be an important phenomenon in the manipulation of the local inflammatory response in periodontitis. In this study, we present mirolysin, a novel metalloproteinase secreted by Tannerella forsythia, a well-recognized pathogen strongly associated with periodontitis. Mirolysin exhibited a strong effect on all complement pathways. It inhibited the classical and lectin complement pathways due to efficient degradation of mannose-binding lectin, ficolin-2, ficolin-3, and C4, whereas inhibition of the alternative pathway was caused by degradation of C5. This specificity toward complement largely resembled the activity of a previously characterized metalloproteinase of T. forsythia, karilysin. Interestingly, mirolysin released the biologically active C5a peptide in human plasma and induced migration of neutrophils. Importantly, we demonstrated that combination of mirolysin with karilysin, as well as a cysteine proteinase of another periodontal pathogen, Prevotella intermedia, resulted in a strong synergistic effect on complement. Furthermore, mutant strains of T. forsythia, devoid of either mirolysin or karilysin, showed diminished survival in human serum, providing further evidence for the synergistic inactivation of complement by these metalloproteinases. Taken together, our findings on interactions of mirolysin with complement significantly add to the understanding of immune evasion strategies of T. forsythia and expand the knowledge on molecular mechanisms driving pathogenic events in the infected periodontium.

KW - Animals

KW - Bacterial Proteins

KW - Bacteroides

KW - Bacteroides Infections

KW - Cell Movement

KW - Complement Activation

KW - Complement Pathway, Alternative

KW - Complement Pathway, Classical

KW - Complement Pathway, Mannose-Binding Lectin

KW - Complement System Proteins

KW - Hemolysis

KW - Host-Pathogen Interactions

KW - Humans

KW - Matrix Metalloproteinases

KW - Metalloproteases

KW - Microbial Viability

KW - Mutation

KW - Neutrophils

KW - Periodontitis

KW - Sheep

U2 - 10.4049/jimmunol.1402892

DO - 10.4049/jimmunol.1402892

M3 - Journal article

C2 - 26209620

VL - 195

SP - 2231

EP - 2240

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 5

ER -