Neutralizing alpha-toxin accelerates healing of Staphylococcus Aureus-infected wounds in nondiabetic and diabetic mice

Roger V. Ortines, Haiyun Liu, Lily I. Cheng, Taylor S. Cohen, Heather Lawlor, Abhishek Gami, Yu Wang, Carly A. Dillen, Nathan K. Archer, Robert J. Miller, Alyssa G. Ashbaugh, Bret L. Pinsker, Mark C. Marchitto, Christine Tkaczyk, C. Kendall Stover, Bret R. Sellman, Lloyd S. Millera

Research output: Contribution to journalArticle

Abstract

Staphylococcus aureus wound infections delay healing and result in invasive complications such as osteomyelitis, especially in the setting of diabetic foot ulcers. In preclinical animal models of S. aureus skin infection, antibody neutralization of alpha-toxin (AT), an S. aureus-secreted pore-forming cytolytic toxin, reduces disease severity by inhibiting skin necrosis and restoring effective host immune responses. However, whether therapeutic neutralization of alpha-toxin is effective against S. aureus-infected wounds is unclear. Herein, the efficacy of prophylactic treatment with a human neutralizing anti-AT monoclonal antibody (MAb) was evaluated in an S. aureus skin wound infection model in nondiabetic and diabetic mice. In both nondiabetic and diabetic mice, anti-AT MAb treatment decreased wound size and bacterial burden and enhanced reepithelialization and wound resolution compared to control MAb treatment. Anti-AT MAb had distinctive effects on the host immune response, including decreased neutrophil and increased monocyte and macrophage infiltrates in nondiabetic mice and decreased neutrophil extracellular traps (NETs) in diabetic mice. Similar therapeutic efficacy was achieved with an active vaccine targeting AT. Taken together, neutralization of AT had a therapeutic effect against S. aureus-infected wounds in both nondiabetic and diabetic mice that was associated with differential effects on the host immune response.

Original languageEnglish (US)
Article numbere02288-17
JournalAntimicrobial agents and chemotherapy
Volume62
Issue number3
DOIs
StatePublished - Mar 2018

Keywords

  • Alpha-toxin
  • Diabetes
  • HLA
  • Macrophage
  • Monocyte
  • Neutrophil
  • Neutrophil extracellular traps (NETs)
  • Staphylococcus aureus
  • Wound
  • Wound healing
  • Wound infection

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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  • Cite this

    Ortines, R. V., Liu, H., Cheng, L. I., Cohen, T. S., Lawlor, H., Gami, A., Wang, Y., Dillen, C. A., Archer, N. K., Miller, R. J., Ashbaugh, A. G., Pinsker, B. L., Marchitto, M. C., Tkaczyk, C., Stover, C. K., Sellman, B. R., & Millera, L. S. (2018). Neutralizing alpha-toxin accelerates healing of Staphylococcus Aureus-infected wounds in nondiabetic and diabetic mice. Antimicrobial agents and chemotherapy, 62(3), [e02288-17]. https://doi.org/10.1128/AAC.02288-17