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

Ichiro Inoshima1, Naoko Inoshima, Georgia A Wilke

  • 1Department of Pediatrics, University of Chicago, Chicago, Illinois, USA.

Nature Medicine
|September 20, 2011
PubMed

Insights

Staphylococcus aureus alpha-hemolysin causes pneumonia by upregulating ADAM10 activity, leading to E-cadherin cleavage and lung injury. Inhibiting ADAM10 may prevent alpha-hemolysin-induced diseases.

Area of Science:

  • Microbiology
  • Pathogenesis
  • Cell Biology

Background:

  • Staphylococcus aureus is a significant cause of human infections and mortality.
  • Alpha-hemolysin (Hla) is a key virulence factor contributing to S. aureus-induced pneumonia.
  • Hla interacts with its receptor, ADAM10, a metalloprotease, to injure epithelial cells.

Purpose of the Study:

  • To investigate the role of ADAM10 as the cellular receptor for alpha-hemolysin.
  • To elucidate the molecular mechanism by which alpha-hemolysin contributes to pneumonia pathogenesis.
  • To evaluate ADAM10 inhibition as a therapeutic strategy against alpha-hemolysin-induced lung injury.

Main Methods:

  • Utilized mice with conditional Adam10 gene disruption in lung epithelium.
  • Investigated the molecular interaction between alpha-hemolysin and ADAM10.
  • Assessed the effect of alpha-hemolysin on ADAM10 activity and E-cadherin cleavage.
  • Examined the impact of a metalloprotease inhibitor on toxin-induced effects.
  • Analyzed toxin-dependent epithelial barrier disruption in ADAM10-knockout models.

Main Results:

  • Mice with Adam10 disruption in lung epithelium were resistant to lethal pneumonia.
  • Alpha-hemolysin upregulates ADAM10 metalloprotease activity in alveolar epithelial cells.
  • This upregulation leads to the cleavage of E-cadherin, a crucial adherens junction protein.
  • E-cadherin cleavage disrupts epithelial barrier function, contributing to acute lung injury.
  • ADAM10 inhibition prevented E-cadherin cleavage and attenuated barrier disruption.

Conclusions:

  • ADAM10 functions as the cellular receptor for alpha-hemolysin.
  • Alpha-hemolysin exploits ADAM10's metalloprotease activity, revealing a novel mechanism of cytotoxin action.
  • ADAM10 inhibition represents a promising therapeutic strategy to mitigate alpha-hemolysin-mediated diseases.

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