Staphylococcus aureus is a leading cause of human skin infections, contributing to disease in both healthy and immunocompromised individuals, also complicating burn and surgical wound sites and lesions of atopic dermatitis (Lowy, 1998; Ong and Leung, 2010). Host defense against staphylococcal skin infection is multifaceted, relying on local immunologic control through TH17 and IL-1β–driven recruitment of neutrophils in addition to the protective actions of antimicrobial peptides and physical properties of the cutaneous barrier (Miller and Cho, 2011). Pathogen virulence in staphylococcal skin infection is likewise multifactorial (Weidenmaier et al., 2010), relying in part on the action of α-hemolysin, a pore-forming cytotoxin secreted by almost all strains of S. aureus. Hla is required for dermonecrotic changes during infection, also contributing to abscess size (Kennedy et al., 2010). Immunization strategies targeting Hla protect against dermonecrosis (Kennedy et al., 2010), however the molecular mechanism by which the toxin causes pathologic disturbance of the epithelial barrier is ill-understood.

We recently identified the zinc-dependent metalloprotease ADAM10 as the cellular receptor for Hla (Wilke and Bubeck Wardenburg, 2010). ADAM10 regulates epithelial function through its ability to cleave E-cadherin, severing the protein-based adherens junction tether between adjacent cells (Maretzky et al., 2005). ADAM10 knockout mice exhibit embryonic lethality (Hartmann et al., 2002), while conditional skin knockout of ADAM10 during gestation or in the postnatal epidermis results in marked dysregulation of epithelial differentiation and barrier function (Weber et al., 2011). To examine the contribution of ADAM10 to skin infection, we generated conditional knockout mice in which exon 3 of ADAM10 is flanked by loxP sites (Tian et al., 2008), excised in the presence of a Cre recombinase expressed under control of the keratin 14 promoter (Vasioukhin et al., 1999). Topical application of tamoxifen (TAM) to a 1cm2 skin area for 5 days leads to localized ADAM10 genomic excision (Fig. S1a and b), abrogating epidermal ADAM10 expression