Staphylococcus aureus resists human defensins by production of staphylokinase, a novel bacterial evasion mechanism.
Alpha-defensins are peptides secreted by polymorphonuclear cells and provide antimicrobial protection mediated by disruption of the integrity of bacterial cell walls. Staphylokinase is an exoprotein produced by Staphylococcus aureus, which activates host plasminogen. In this study, we analyzed the impact of interaction between alpha-defensins and staphylokinase on staphylococcal growth. We observed that staphylokinase induced extracellular release of alpha-defensins from polymorphonuclear cells. Moreover, a direct binding between alpha-defensins and staphylokinase was shown to result in a complex formation. The biological consequence of this interaction was an almost complete inhibition of the bactericidal effect of alpha-defensins. Notably, staphylokinase with blocked plasminogen binding site still retained its ability to neutralize the bactericidal effect of alpha-defensins. In contrast, a single mutation of a staphylokinase molecule at position 74, substituting lysine for alanine, resulted in a 50% reduction of its alpha-defensin-neutralizing properties. The bactericidal properties of alpha-defensins were tested in 19 S. aureus strains in vitro and in a murine model of S. aureus arthritis. Staphylococcal strains producing staphylokinase were protected against the bactericidal effect of alpha-defensins. When staphylokinase was added to staphylokinase-negative S. aureus cultures, it almost totally abrogated the effect of alpha-defensins. Finally, human neutrophil peptide 2 injected intra-articularly along with bacteria alleviated joint destruction. In this study, we report a new property of staphylokinase, its ability to induce secretion of defensins, to complex bind them and to neutralize their bactericidal effect. Staphylokinase production may therefore be responsible in vivo for defensin resistance during S. aureus infections.
Jin
Tao
T
Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Guldhedsgatan 10, S-413 46 Göteborg, Sweden.
Bokarewa
Maria
M
Foster
Timothy
T
Mitchell
Jennifer
J
Higgins
Judy
J
Tarkowski
Andrej
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009297:Nasal Mucosa / Q000201:enzymology / Q000382:microbiology; D009504:Neutrophils / Q000378:metabolism / Q000382:microbiology; D010958:Plasminogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000254:growth & development / Q000276:immunology* / Q000302:isolation & purification; D023084:alpha-Defensins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology* / Q000627:therapeutic use
D011994:Recombinant Proteins; D023084:alpha-Defensins; D010958:Plasminogen; D008666:Metalloendopeptidases; C022653:auR protein, Staphylococcus aureus