A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice

作者：Inoshima Ichiro; Inoshima Naoko; Wilke Georgia A; Powers Michael E; Frank Karen M; Wang Yang; Wardenburg Juliane Bubeck^*

来源：Nature Medicine, 2011, 17(10): 1310-U196.

DOI：10.1038/nm.2451

Staphylococcus aureus is a major cause of human disease, responsible for half a million infections and approximately 20,000 deaths per year in the United States alone(1,2). This pathogen secretes a-hemolysin, a pore-forming cytotoxin that contributes to the pathogenesis of pneumonia(3-5). alpha-hemolysin injures epithelial cells in vitro by interacting with its receptor, the zinc-dependent metalloprotease ADAM10 ( ref. 6). We show here that mice harboring a conditional disruption of the Adam10 gene in lung epithelium are resistant to lethal pneumonia. Investigation of the molecular mechanism of toxin-receptor function revealed that alpha-hemolysin upregulates ADAM10 metalloprotease activity in alveolar epithelial cells, resulting in cleavage of the adherens junction protein E-cadherin. Cleavage is associated with disruption of epithelial barrier function, contributing to the pathogenesis of lethal acute lung injury. A metalloprotease inhibitor of ADAM10 prevents E-cadherin cleavage in response to Hla; similarly, toxin-dependent E-cadherin proteolysis and barrier disruption is attenuated in ADAM10-knockout mice. Together, these data attest to the function of ADAM10 as the cellular receptor for alpha-hemolysin. The observation that alpha-hemolysin can usurp the metalloprotease activity of its receptor reveals a previously unknown mechanism of pore-forming cytotoxin action in which pathologic insults are not solely the result of irreversible membrane injury and defines ADAM10 inhibition as a strategy to attenuate alpha-hemolysin-induced disease.

• 出版日期2011-10