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

Jusko, Monika LU ; Potempa, Jan; Mizgalska, Danuta; Bielecka, Ewa LU ; Ksiazek, Miroslaw; Riesbeck, Kristian LU ; Garred, Peter; Eick, Sigrun and Blom, Anna LU (2015) In Journal of Immunology 195(5). p.2231-2240
Abstract
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... (More)
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. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
195
issue
5
pages
2231 - 2240
publisher
American Association of Immunologists
external identifiers
  • pmid:26209620
  • wos:000360014200036
  • scopus:84940121367
ISSN
1550-6606
DOI
10.4049/jimmunol.1402892
language
English
LU publication?
yes
id
1bc36031-a1b1-4208-940c-f6699c53c0f7 (old id 7720847)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26209620?dopt=Abstract
date added to LUP
2015-08-10 17:09:36
date last changed
2017-08-27 03:36:01
@article{1bc36031-a1b1-4208-940c-f6699c53c0f7,
  abstract     = {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.},
  author       = {Jusko, Monika and Potempa, Jan and Mizgalska, Danuta and Bielecka, Ewa and Ksiazek, Miroslaw and Riesbeck, Kristian and Garred, Peter and Eick, Sigrun and Blom, Anna},
  issn         = {1550-6606},
  language     = {eng},
  number       = {5},
  pages        = {2231--2240},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {A Metalloproteinase Mirolysin of Tannerella forsythia Inhibits All Pathways of the Complement System.},
  url          = {http://dx.doi.org/10.4049/jimmunol.1402892},
  volume       = {195},
  year         = {2015},
}