Neutralizing {alpha}-toxin accelerates healing of Staphylococcus aureus-infected wounds in normal and diabetic mice [PublishAheadOfPrint]

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 α-toxin (AT), a 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 α-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 a S. aureus skin wound infection model in non-diabetic and diabetic mice. In both non-diabetic and diabetic mice, anti-AT mAb treatment decreased wound sizes and bacterial burden and enhanced reepithelialization and wound resolution compared with control mAb. Anti-AT mAb had distinctive effects on the host immune response, including decreased neutrophil and increased monocyte and macrophage infiltrates in non-diabetic 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 non-diabetic and diabetic mice that was associated with differential effects on the host immune response.

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