α-haemolysin, a pore-forming toxin produced by Staphylococcus aureus, was recently shown to bind the host cell metalloproteinase ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10). Bubeck Wardenburg and colleagues now find that this interaction is key to barrier disruption in epithelial cells during infection.

it is possible that the activity of ADAM10 is usurped by a broad range of bacteria

To investigate the role of ADAM10 in S. aureus-mediated pneumonia, the authors generated mice that lacked this protein specifically in the respiratory epithelium. On infection with S. aureus, these mice did not develop severe pneumonia, showing greater preservation of lung tissue and less inflammation than control mice. However, they did not show a reduced bacterial burden, indicating that ADAM10 has a role specifically in epithelial injury.

ADAM10 triggers the cleavage of E-cadherin, leading to breakdown of cell–cell junctions, so the authors reasoned that this may be the mechanism by which α-haemolysin promotes epithelial barrier disruption. Accordingly, epithelial cells treated with α-haemolysin showed increased metalloproteinase activity, E-cadherin cleavage and rapid loss of barrier function in vitro. By contrast, metalloproteinase activity in cells lacking ADAM10 was markedly reduced and barrier function was normal.

The authors assessed the relevance of their findings in vivo. In contrast to mice infected with wild-type S. aureus, those infected with α-haemolysin-deficient bacteria showed decreased levels of barrier disruption and had lower levels of the E-cadherin amino-terminal fragment (generated following cleavage of the full-length protein) in the lungs. Moreover, α-haemolysin treatment did not induce E-cadherin cleavage in mice lacking ADAM10 in the respiratory epithelium, confirming that ADAM10 has a key role in mediating the effects of the toxin. Importantly, treating mice with an ADAM10 inhibitor following challenge with α-haemolysin prevented E-cadherin cleavage; this inhibitor also protected mice from lethal pneumonia following infection with S. aureus.

This study reveals a crucial role for ADAM10 in mediating pathogenesis during S. aureus infection. Interestingly, the authors report that ADAM10 can also be used by pneumolysin, a Streptococcus pneumoniae toxin, to trigger E-cadherin cleavage. Therefore, it is possible that the activity of ADAM10 is usurped by a broad range of bacteria, making it a potential therapeutic target.