Staphylococcal complement evasion by various convertase-blocking molecules.
To combat the human immune response, bacteria should be able to divert the effectiveness of the complement system. We identify four potent complement inhibitors in Staphylococcus aureus that are part of a new immune evasion cluster. Two are homologues of the C3 convertase modulator staphylococcal complement inhibitor (SCIN) and function in a similar way as SCIN. Extracellular fibrinogen-binding protein (Efb) and its homologue extracellular complement-binding protein (Ecb) are identified as potent complement evasion molecules, and their inhibitory mechanism was pinpointed to blocking C3b-containing convertases: the alternative pathway C3 convertase C3bBb and the C5 convertases C4b2aC3b and C3b2Bb. The potency of Efb and Ecb to block C5 convertase activity was demonstrated by their ability to block C5a generation and C5a-mediated neutrophil activation in vitro. Further, Ecb blocks C5a-dependent neutrophil recruitment into the peritoneal cavity in a mouse model of immune complex peritonitis. The strong antiinflammatory properties of these novel S. aureus-derived convertase inhibitors make these compounds interesting drug candidates for complement-mediated diseases.
Jongerius
Ilse
I
Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands. i.jongerius@umcutrecht.nl
Köhl
Jörg
J
Pandey
Manoj K
MK
Ruyken
Maartje
M
van Kessel
Kok P M
KP
van Strijp
Jos A G
JA
Rooijakkers
Suzan H M
SH
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D050577:Complement C3-C5 Convertases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism*; D004765:Enteropeptidase / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009504:Neutrophils / Q000166:cytology; D013211:Staphylococcus aureus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
D001426:Bacterial Proteins; D037521:Virulence Factors; C587010:extracellular complement binding protein, Staphylococcus aureus; D003165:Complement System Proteins; D050577:Complement C3-C5 Convertases; D004765:Enteropeptidase