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Updated: Jan 8, 2026
Subcutaneous Infection of Methicillin Resistant Staphylococcus Aureus MRSA
Published on: February 9, 2011
α-hemolysin polymorphisms in methicillin-resistant Staphylococcus aureus clinical isolates regulate ADAM10-dependent
Karl Liboro1, Jolynn T Chau2, James D Begando1
1Department of Physiology and Biophysics.
Abstract:
Staphylococcus aureus α-hemolysin (Hla) is a major virulence factor that utilizes cell surface ADAM10 to oligomerize and form a functional heptameric pore. We show here that Hla from strain USA300 is required to induce IL-1β secretion by neutrophils and to cause severe corneal disease in mice. We also demonstrate that in contrast to USA300 and other clonal complex 8 (CC8) methicillin resistant S. aureus (MRSA) isolated from the skin, CC5 Hla from corneas of infected patients have single nucleotide polymorphisms (SNP) that result in two amino acid substitutions, D208E (Asp-Glu) and I275T (Ile-Thr). Structural modeling predicts CC5 Hla self-assembly and altered binding to ADAM10 that is distinct from CC8 Hla. The ADAM10 inhibitor GI254023X blocked neutrophil IL-1β secretion induced by Hla-expressing CC8, but not by CC5 conditioned media, indicating that these Hla polymorphisms play an important role in Hla receptor binding and neutrophil IL-1β secretion, and affect corneal disease severity.
Insights
Staphylococcus aureus alpha-hemolysin (Hla) variants from different strains cause distinct IL-1β secretion and corneal disease severity. Specific Hla polymorphisms influence receptor binding and neutrophil responses.
Area of Science:
- Microbiology
- Immunology
- Ophthalmology
Background:
- Staphylococcus aureus alpha-hemolysin (Hla) is a key virulence factor.
- Hla oligomerizes on cell surfaces via ADAM10 to form pores.
- Hla contributes to neutrophil activation and tissue damage.
Purpose of the Study:
- To investigate the role of Hla variants in neutrophil activation and corneal disease.
- To compare Hla from different Staphylococcus aureus strains (CC8 vs. CC5).
- To elucidate the impact of Hla polymorphisms on ADAM10 binding and function.
Main Methods:
- Comparative analysis of Hla from USA300 (CC8) and CC5 strains.
- Induction of IL-1β secretion in neutrophils using Hla.
- Mouse model of corneal disease.
- Structural modeling of Hla variants.
- Inhibition studies using ADAM10 inhibitor GI254023X.
Main Results:
- Hla from USA300 (CC8) induced IL-1β secretion and severe corneal disease.
- CC5 Hla exhibited unique amino acid substitutions (D208E, I275T) compared to CC8 Hla.
- Structural modeling suggested altered CC5 Hla self-assembly and ADAM10 binding.
- ADAM10 inhibition blocked CC8 Hla-induced IL-1β secretion but not CC5 Hla-induced secretion.
Conclusions:
- Hla polymorphisms in CC5 strains significantly alter Hla function.
- These polymorphisms affect Hla receptor binding and neutrophil IL-1β secretion.
- Hla variants contribute to varying severity of corneal disease caused by Staphylococcus aureus.
