Alpha hemolysin polymorphisms in methicillin-resistant Staphylococcus aureus clinical isolates regulate ADAM10-dependent neutrophil IL-1 beta secretion

Liboro, K.; Chau, J. T.; Begando, J.; Abbodante, S.; Lackner, A.; Marshall, M. E.; Sun, Y.; Ly, N.; Dubyak, G. R.; Gilmore, M.; McNulty, R.; Andre, C.; Pearlman, E. S.

doi:10.64898/2025.12.13.694139

bioRxiv · 10.64898/2025.12.13.694139

Alpha hemolysin polymorphisms in methicillin-resistant Staphylococcus aureus clinical isolates regulate ADAM10-dependent neutrophil IL-1 beta secretion

Liboro, K.·Chau, J. T.·Begando, J.·Abbodante, S.·Lackner, A.·Marshall, M. E.·Sun, Y.·Ly, N.·Dubyak, G. R.·Gilmore, M.·McNulty, R.·Andre, C.·Pearlman, E. S.

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Abstract

Staphylococcus aureus -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-1{beta} 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-1{beta} 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-1{beta} secretion, and affect corneal disease severity.

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Liboro, K., Chau, J. T., Begando, J., Abbodante, S., Lackner, A., Marshall, M. E., Sun, Y., Ly, N., Dubyak, G. R., Gilmore, M., McNulty, R., Andre, C., Pearlman, E. S.. 2025-12-14. Alpha hemolysin polymorphisms in methicillin-resistant Staphylococcus aureus clinical isolates regulate ADAM10-dependent neutrophil IL-1 beta secretion. https://doi.org/10.64898/2025.12.13.694139

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