title: A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice.
abstract: 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. This pathogen secretes α-hemolysin, a pore-forming cytotoxin that contributes to the pathogenesis of pneumonia. α-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 α-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 α-hemolysin. The observation that α-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 α-hemolysin-induced disease.
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois, USA.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Inoshima
authors.forename: Naoko
authors.initials: N
authors.lastname: Inoshima
authors.forename: Georgia A
authors.initials: GA
authors.lastname: Wilke
authors.forename: Michael E
authors.initials: ME
authors.lastname: Powers
authors.forename: Karen M
authors.initials: KM
authors.lastname: Frank
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Juliane
authors.initials: J
authors.lastname: Bubeck Wardenburg
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism / Q000506:poisoning*; D018893:Bronchoalveolar Lavage; D015820:Cadherins / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics* / Q000502:physiology; D006460:Hemolysin Proteins / Q000378:metabolism / Q000506:poisoning*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011014:Pneumonia / Q000235:genetics*; D013211:Staphylococcus aureus / Q000737:chemistry*
chemical_list: D001427:Bacterial Toxins; D015820:Cadherins; D006460:Hemolysin Proteins; D008565:Membrane Proteins; C021091:staphylococcal alpha-toxin; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse