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Blood, 15 June 2001, Vol. 97, No. 12, pp. 3790-3797
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Activation of protease-activated receptors by gingipains from
Porphyromonas gingivalis leads to platelet aggregation: a
new trait in microbial pathogenicity
Afrodite Lourbakos,
YuPing Yuan,
Alison L. Jenkins,
James Travis,
Patricia Andrade-Gordon,
Rosemary Santulli,
Jan Potempa, and
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.
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.
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Related Letter in Blood Online:
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A growing set of platelet-activating bacterial proteins
- James P. McRedmond, Desmond J. Fitzgerald ;, Robert N. Pike, Afrodite Lourbakos, James Travis, and Jan Potempa
Blood 2002 99: 387-388.
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