Activation of protease-activated receptors by gingipains fromPorphyromonas gingivalis leads to platelet aggregation: a new trait in microbial pathogenicity

• Afrodite Lourbakos

  From the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia; the Department of Medicine, Monash University, Box Hill, Victoria, Australia; the Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA; Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Springhouse, PA; and the Departments of Microbiology and Immunology, Jagiellonian University, Krakow, Poland.

• YuPing Yuan

  From the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia; the Department of Medicine, Monash University, Box Hill, Victoria, Australia; the Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA; Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Springhouse, PA; and the Departments of Microbiology and Immunology, Jagiellonian University, Krakow, Poland.

• Alison L. Jenkins

  From the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia; the Department of Medicine, Monash University, Box Hill, Victoria, Australia; the Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA; Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Springhouse, PA; and the Departments of Microbiology and Immunology, Jagiellonian University, Krakow, Poland.

• James Travis

  From the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia; the Department of Medicine, Monash University, Box Hill, Victoria, Australia; the Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA; Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Springhouse, PA; and the Departments of Microbiology and Immunology, Jagiellonian University, Krakow, Poland.

• Patricia Andrade-Gordon

  From the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia; the Department of Medicine, Monash University, Box Hill, Victoria, Australia; the Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA; Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Springhouse, PA; and the Departments of Microbiology and Immunology, Jagiellonian University, Krakow, Poland.

• Rosemary Santulli

  From the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia; the Department of Medicine, Monash University, Box Hill, Victoria, Australia; the Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA; Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Springhouse, PA; and the Departments of Microbiology and Immunology, Jagiellonian University, Krakow, Poland.

• Jan Potempa

  From the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia; the Department of Medicine, Monash University, Box Hill, Victoria, Australia; the Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA; Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Springhouse, PA; and the Departments of Microbiology and Immunology, Jagiellonian University, Krakow, Poland.

• Robert N. Pike

  From the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia; the Department of Medicine, Monash University, Box Hill, Victoria, Australia; the Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA; Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Springhouse, PA; and the Departments of Microbiology and Immunology, Jagiellonian University, Krakow, Poland.

抄録

The bacterium Porphyromonas gingivalis is a major etiologic agent in the pathogenesis of adult periodontitis in humans. Cysteine proteinases produced by this pathogen, termed gingipains, are considered to be important virulence factors. Among many other potentially deleterious activities, arginine-specific gingipains-R (RgpB and HRgpA) efficiently activate coagulation factors. To further expand knowledge of the interaction between gingipains and the clotting cascade, this study examined their effects on cellular components of the coagulation system. The enzymes induced an increase in intracellular calcium in human platelets at nanomolar concentrations and caused platelet aggregation with efficiency comparable to thrombin. Both effects were dependent on the proteolytic activity of the enzymes. Based on desensitization studies carried out with thrombin and peptide receptor agonists, and immunoinhibition experiments, gingipains-R appeared to be activating the protease-activated receptors, (PAR)-1 and -4, expressed on the surface of platelets. This was confirmed by the finding that HRgpA and RgpB potently activated PAR-1 and PAR-4 in transfected cells stably expressing these receptors. Cumulatively, the results indicate the existence of a novel pathway of host cell activation by bacterial proteinases through PAR cleavage. This mechanism not only represents a new trait in bacterial pathogenicity, but may also explain an emerging link between periodontitis and cardiovascular disease.

収録刊行物

• Blood

  Blood 97 (12), 3790-3797, 2001-06-15

  American Society of Hematology

キーワード

• Cell Biology
• Hematology
• Immunology
• Biochemistry

詳細情報

• CRID: 1363951795871201920
• NII論文ID: 30022493748
• DOI: 10.1182/blood.v97.12.3790
• ISSN: 15280020
• ISSN: 00064971
• Web Site: http://ashpublications.org/blood/article-pdf/97/12/3790/1674921/h8120103790.pdf
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