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 (1,2). This pathogen secretes α-hemolysin, a pore-forming cytotoxin that contributes to the pathogenesis of pneumonia (3–5). α-hemolysin injures epithelial cells by interacting with its receptor, the zinc-dependent metalloprotease ADAM10 (6). We show 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; similarly, 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 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 ADAM10 inhibition as a strategy for disease modification.
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Hla contributes to barrier dysfunction in A549 cells through interaction with ADAM-10 and cleavage of E-cadherin.
“Hla also contributes to barrier dysfunction in A549 cells through its interaction with ADAM-10 and cleavage of E-cadherin [27].”
From Staphylococcus aureus activation of caspase 1/calpain signaling mediates invasion through human keratinocytes (2012) · cites this paper as [27]
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- Authors
- Inoshima, I., Inoshima, N., Wilke, G. A., Powers, M. E., Frank, K. M., Wang, Y., & Wardenburg, J. B.
- Affiliations
- Kyushu University (JP)
- University of Chicago (US)
- Venue
- Nature Medicine
- Published
- 2011-09-18
- Volume
- 17
- Issue
- 10
- Pages
- 1310-1314
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3192248
- OpenAlex
- W1807126837
- Cited by
- 21
- References
- 32
- Citations by year
- 2026: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 5 · 2017: 1 · 2016: 1 · 2014: 1 · 2013: 2 · 2012: 4
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- European Respiratory Journal (publishedVersion)
- PubMed (publishedVersion)
- European Respiratory Journal
- Funders
- National Institute of General Medical Sciences (T32GM007183)
- National Institute of Allergy and Infectious Diseases (U54AI057153)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
- Keywords
- Staphylococcus aureus, alpha-hemolysin, pore-forming toxins, ADAM10, E-cadherin cleavage, adherens junctions, epithelial barrier function, acute lung injury, pneumonia, toxin receptor, metalloprotease inhibition, alveolar epithelial cells, conditional knockout mice
- MeSH terms
- ADAM10 Protein, Animals, Bacterial Toxins, Epithelium, Hemolysin Proteins, Membrane Proteins, Pneumonia, Staphylococcus aureus, Cadherins, Gene Expression Regulation, Bacterial, Mice, Knockout, Bronchoalveolar Lavage, Mice, ADAM Proteins, Amyloid Precursor Protein Secretases
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