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Abstract

Alpha toxin (AT) is a major virulence factor in Staphylococcus aureus disease pathogenesis. We previously identified a monoclonal antibody (mAb) against AT that reduced disease severity in a mouse dermonecrosis model. Herein, we evaluated the activity of an affinity optimized variant, LC10, in a mouse S. aureus pneumonia model. Passive immunization with LC10 increased survival, reduced bacterial numbers in the lungs and kidneys of infected mice and showed protection against diverse clinical isolates. Lungs from S. aureus infected mice exhibited bacterial pneumonia including widespread inflammation whereas lungs from mice that received LC10 exhibited minimal inflammation and retained healthy lung architecture. Consistent with reduced immune cell infiltration, LC10 treated animals had significantly lower (p<0.05) proinflammatory cytokine and chemokine levels in the bronchoalveolar lavage fluid relative control treated animals. This reduction in inflammation and damage in the LC10 treated animals resulted in reduced vascular protein leakage and CO2 levels in the blood. LC10 was also assessed for therapeutic activity in combination with vancomycin or linezolid. Treatment with a combination of LC10 and vancomycin or linezolid resulted in a significant increase (p<0.05) in survival relative to the monotherapies and was deemed additive to synergistic by isobologram analysis. Consistent with improved survival, lungs from animals treated with antibiotic + LC10 exhibited less inflammatory tissue damage than those that received either monotherapy. These data provide insight into the mechanisms of protection provided by AT inhibition and support AT as a promising target for immunoprophylaxis or adjunctive therapy against S. aureus pneumonia.