Activation of TAFI on the surface of Streptococcus pyogenes evokes inflammatory reactions by modulating the kallikrein/kinin system.
Bacteria-controlled regulation of host responses to infection is an important virulence mechanism that has been demonstrated to contribute to disease progression. Here we report that the human pathogen Streptococcus pyogenes employs the procarboxypeptidase TAFI (thrombin-activatable fibrinolysis inhibitor) to modulate the kallikrein/kinin system. To this end, bacteria initiate a chain of events starting with the recruitment and activation of TAFI. This is followed by the assembly and induction of the contact system at the streptococcal surface, eventually triggering the release of bradykinin (BK). BK is then carboxyterminally truncated by activated TAFI, which converts the peptide from a kinin B(2) receptor ligand to a kinin B(1) receptor (B1R) agonist. Finally, we show that streptococcal supernatants indirectly amplify the B1R response as they act on peripheral blood mononuclear cells to secrete inflammatory cytokines that in turn stimulate upregulation of the B1R on human fibroblasts. Taken together our findings implicate a critical and novel role for streptococci-bound TAFI, as it processes BK to a B1R agonist at the bacterial surface and thereby may redirect inflammation from a transient to a chronic state.
Bengtson
Sara H
SH
Department of Clinical Sciences, Section for Clinical and Experimental Infection Medicine, Lund University, Lund, Sweden. Sara.Mattsson@med.lu.se
Sandén
Caroline
C
Mörgelin
Matthias
M
Marx
Pauline F
PF
Olin
Anders I
AI
Leeb-Lundberg
L M Fredrik
LM
Meijers
Joost C M
JC
Herwald
Heiko
H
D001920:Bradykinin / Q000378:metabolism*; D025901:Carboxypeptidase B2 / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000382:microbiology*; D016234:Kallikrein-Kinin System / Q000276:immunology*; D008168:Lung / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000276:immunology; D013297:Streptococcus pyogenes / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
D016207:Cytokines; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D025901:Carboxypeptidase B2; D001920:Bradykinin