Neutralizing Alpha-Toxin Accelerates Healing of Staphylococcus aureus-Infected Wounds in Nondiabetic and Diabetic Mice

Abstract

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 skin infection, antibody neutralization of alpha-toxin (AT), an-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 -infected wounds is unclear. Herein, the efficacy of prophylactic treatment with a human neutralizing anti-AT monoclonal antibody (MAb) was evaluated in an 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 -infected wounds in both nondiabetic and diabetic mice that was associated with differential effects on the host immune response.

Staphylococcus aureus Alpha-Toxin Limits Type 1 While Fostering Type 3 Immune Responses

“…To assess the impact of alpha-toxin on CD4 + T cells in vivo , we have utilized a S. aureus bacteremia model, and in contrast to already published studies involving skin, wound or pulmonary infection models ( 46 – 48 ), bloodstream infection with wildtype S. aureus or an isogenic Δhla mutant strain caused similar disease severity as measured by body weight and survival, indicating comparable virulence of the two strains in this setting. Interestingly, we could recapitulate the in vitro finding by demonstrating a decreased frequency of T-bet + CD4 + T cells when wildtype-infected were compared to Δhla-infected animals, while significantly increased frequencies of RORγt + CD4 + T cells were observed upon infection with both strains.…”

Alpha-Toxin Contributes to Biofilm Formation among Staphylococcus aureus Wound Isolates

“…Two published preclinical animal studies support the potential clinical benefits of neutralizing AT in a SA infected wound. One study determined that prophylactic treatment with anti-AT mAb-MEDI4893* in a SA skin wound murine infection model decreased wound size, bacterial burden, enhanced re-epithelialization and wound resolution compared to a control mAb [ 35 ]. Additionally, combined treatment with MEDI4893* and an antibiotic, compared to antibiotics alone, improved disease outcome and accelerated wound healing in an SA murine dermonecrosis model [ 36 ].…”

Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens

“…The antibody targets the secreted alpha-toxin and prevents the bacterium's ability to cause apoptosis in cells, which, in turn, prevents lysis and tissue necrosis caused by S. aureus infection. Further, the antibody has been shown to prevent necrosis in other clinical indications such as surgical site and wound infection models [52][53][54]. Recently, MEDI4893 was shown to improve lung function in patients with S. aureus infections in a successful Phase 2 trial, and the results were presented earlier this year (ASM Microbe, 2019, San Francisco).…”