Interferon-γ protects from staphylococcal alpha toxin induced keratinocyte death through apolipoprotein L1

Staphylococcus aureus is a bacterial pathogen that frequently infects the skin, causing lesions and cell destruction through its primary virulence factor, alpha-toxin. Here we show that interferon gamma (IFN-γ) protects human keratinocytes from cell death induced by staphylococcal alpha toxin. We find that IFN-γ prevents alpha toxin binding and reduces expression of the alpha toxin receptor, ADAM10. We determine that the mechanism for IFN-γ mediated resistance to alpha toxin involves the induction of autophagy, a process of cellular adaptation to sublethal damage. We find that IFN-γ potently stimulates activation of the primary autophagy effector, LC3. This process is dependent upon up-regulation of Apolipoprotein L1 (ApoL1). Depletion of ApoL1 by siRNA significantly increases alpha toxin induced lethality and inhibits activation of LC3. We conclude that IFN-γ plays a significant role to protect human keratinocytes from the lethal effects of staphylococcal alpha toxin through ApoL1 induced autophagy.