RT Journal Article
SR Electronic
T1 A staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P2542
VO 44
IS Suppl 58
A1 Ichiro Inoshima
A1 Juliane Bubeck Wardenburg
A1 Naoko Inoshima
A1 Georgia Wilke
A1 Micheal Powers
A1 Karen Frank
A1 Hironori Mikumo
A1 Yuichi Mizuta
A1 Yoichi Nakanishi
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/P2542.abstract
AB Staphylococcus aureus secretes α-hemolysin, a pore-forming cytotoxin that contributes to the pathogenesis of pneumonia. α-hemolysin injures epithelial cells by interacting with the zinc-dependent metalloprotease ADAM10 as its receptor5. We show that conditional knock out mice of Adam10 in the lung epithelium are highly 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 causes a disruption of epithelial barrier function, contributing to the pathogenesis of acute lung injury.A specific metalloprotease inhibitor of ADAM10 prevents toxin-induced E-cadherin cleavage; similarly, E- cadherin proteolysis and barrier disruption is attenuated in ADAM10 knockout mice.The observation that Hla can usurp the metalloprotease activity of its receptor reveals a novel mechanism of pore-forming cytotoxin action in which pathologic insults are not solely the result of irreversible membrane injury, and defines inhibition of ADAM10 activity as a strategy for disease modification.