Background. Staphylococcus aureus ␣-toxin is a major virulence factor, but its mechanism of action in vivo is incompletely understood. Methods. We examined the role of ␣-toxin in S. aureus pneumonia using the mouse model of intranasal lung infection with S. aureus strain 8325-4 (hla ϩ S. aureus) and an ␣-toxindeficient mutant strain made on the 8325-4 background (hla Ϫ S. aureus). Results. Intranasal infection of mice with hla Ϫ S. aureus resulted in substantially less lung injury and

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... on, pulmonary edema, and tissue bacterial burden than did infection with hla ϩ S. aureus. Furthermore, fewer mice infected with hla Ϫ S. aureus died of the infection, compared with those infected with hla ϩ S. aureus. Levels of the CXC chemokines keratinocyte-derived chemokine and macrophage inflammatory protein-2 were significantly lower in the airways of mice infected with hla Ϫ S. aureus, and this difference was the result of reduced secretion of newly synthesized chemokines into the airway. Consistent with these data, significantly fewer neutrophils were present in the airways and lungs of mice infected with hla Ϫ S. aureus, compared with those infected with hla ϩ S. aureus. Conclusions. These data suggest that ␣-toxin enhances virulence by facilitating the generation of CXC chemokine gradients and stimulating chemokine-induced neutrophil influx in S. aureus pneumonia.