Counter inhibition between leukotoxins attenuates Staphylococcus aureus virulence.
Staphylococcus aureus subverts host defences by producing a collection of virulence factors including bi-component pore-forming leukotoxins. Despite extensive sequence conservation, each leukotoxin has unique properties, including disparate cellular receptors and species specificities. How these toxins collectively influence S. aureus pathogenesis is unknown. Here we demonstrate that the leukotoxins LukSF-PV and LukED antagonize each other's cytolytic activities on leukocytes and erythrocytes by forming inactive hybrid complexes. Remarkably, LukSF-PV inhibition of LukED haemolytic activity on both human and murine erythrocytes prevents the release of nutrients required for in vitro bacterial growth. Using in vivo murine models of infection, we show that LukSF-PV negatively influences S. aureus virulence and colonization by inhibiting LukED. Thus, while S. aureus leukotoxins can certainly injure immune cells, the discovery of leukotoxin antagonism suggests that they may also play a role in reducing S. aureus virulence and maintaining infection without killing the host.
Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
Pauline
P
Yoong
Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
Victor J
VJ
Torres
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism / Q000494:pharmacology; D001427:Bacterial Toxins / Q000378:metabolism / Q000494:pharmacology; D016923:Cell Death; D002460:Cell Line; D004912:Erythrocytes / Q000187:drug effects; D005098:Exotoxins / Q000378:metabolism / Q000494:pharmacology; D042381:Granulocyte Precursor Cells / Q000187:drug effects; D006801:Humans; D007956:Leukocidins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009504:Neutrophils / Q000187:drug effects; D013203:Staphylococcal Infections / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000378:metabolism*; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism* / Q000494:pharmacology
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D005098:Exotoxins; D007956:Leukocidins; C115218:LukD protein, Staphylococcus aureus; C115217:LukE protein, Staphylococcus aureus; C078284:Panton-Valentine leukocidin; D037521:Virulence Factors; C108483:leukocidin S-component protein, Staphylococcus; C074300:LukF protein, Staphylococcus aureus