Streptococcal cysteine proteinase releases kinins: a virulence mechanism.
Previous work has indicated a crucial role for the extracellular cysteine proteinase of Streptococcus pyogenes in the pathogenicity and virulence of this important human pathogen. Here we find that the purified streptococcal cysteine proteinase releases biologically active kinins from their purified precursor protein, H-kininogen, in vitro, and from kininogens present in the human plasma, ex vivo. Kinin liberation in the plasma is due to the direct action of the streptococcal proteinase on the kininogens, and does not involve the previous activation of plasma prekallikrein, the physiological plasma kininogenase. Judged from the amount of released plasma kinins the bacterial proteinase is highly efficient in its action. This is also the case in vivo. Injection of the purified cysteine proteinase into the peritoneal cavity of mice resulted in a progressive cleavage of plasma kininogens and the concomitant release of kinins over a period of 5 h. No kininogen degradation was seen in mice when the cysteine proteinase was inactivated by the specific inhibitor, Z-Leu-Val-Gly-CHN2, before administration. Intraperitoneal administration into mice of living S. pyogenes bacteria producing the cysteine proteinase induced a rapid breakdown of endogenous plasma kininogens and release of kinins. Kinins are hypotensive, they increase vascular permeability, contract smooth muscle, and induce fever and pain. The release of kinins by the cysteine proteinase of S. pyogenes could therefore represent an important and previously unknown virulence mechanism in S. pyogenes infections.
Herwald
H
H
Department of Cell and Molecular Biology, Lund University, Sweden.
Collin
M
M
Müller-Esterl
W
W
Björck
L
L
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D007704:Kininogens / Q000378:metabolism*; D007705:Kinins / Q000378:metabolism*; D051379:Mice; D011288:Prekallikrein / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D013297:Streptococcus pyogenes / Q000201:enzymology / Q000472:pathogenicity*; D013379:Substrate Specificity
D004792:Enzyme Precursors; D007704:Kininogens; D007705:Kinins; D011498:Protein Precursors; C046022:prekininogens; D011288:Prekallikrein; D003546:Cysteine Endopeptidases; D002118:Calcium