Significance

Staphylococcus aureus is a major cause of invasive bacterial infection. One prominent virulence factor is a-toxin, a protein that injures the cell by forming a damaging pore across the cell membrane. We conducted a genetic screen to identify host factors that control susceptibility to a-toxin. We discovered that several components of the adherens junction complex modulate a-toxin cytotoxicity. By eliminating expression of the junctional protein plekstrin-homology domain containing protein 7 (PLEKHA7), cells gained the ability to recover from a-toxin injury and mice lacking PLEKHA7 exhibited improved healing from S. aureus skin infection and enhanced survival of pneumonia. Our data suggest that targeting nonessential host epithelial junction components can reduce S. aureus morbidity by enhancing cellular resilience to a-toxin injury.