591 Pan-caspase inhibition is a novel immunotherapeutic against MRSA skin infections in mice

Abstract

Staphylococcus aureus causes the majority of skin infections, and the emergence of methicillin-resistant S. aureus (MRSA) strains has created a public health threat. There is an unmet clinical need for non-antibiotic immunotherapies to combat MRSA. Herein, the pan-caspase inhibitor Quinoline-Val-Asp-Difluorophenoxymethyl ketone (Q-VD-OPH) was investigated for efficacy against an MRSA skin infection in mice. A single intraperitoneal injection of Q-VD-OPH 4 hour’s post-infection substantially decreased skin lesion sizes and rapidly reduced bacterial burden compared with vehicle or untreated wildtype (wt) mice. Q-VD-OPH inhibited the inflammasome component ASC speck formation and caspase-1-mediated IL-1β production. However, Q-VD-OPH had similar therapeutic efficacy in mice deficient in ASC, IL-1β, caspase-1, or gasdermin D (the inflammasome-activated pore-forming protein). Interestingly, caspase-11-deficient mice treated with inhibitors to caspases 1 and 8 had similar enhanced immunity as Q-VD-OPH, suggesting that the activity of Q-VD-OPH occurred via inhibition of caspases 1, 8, and 11. Furthermore, Q-VD-OPH resulted in less cell death with increased TNF and TNF-producing monocytes/macrophages in the infected skin, which was critical for immunity as Q-VD-OPH had no efficacy in mice deficient in TNF or TNF/IL-1R and anti-TNF antibody-treated wt mice. Finally, Q-VD-OPH also enhanced immunity against Streptococcus pyogenes and Pseudomonas aeruginosa skin infections. Collectively, pan-caspase inhibition represents potential host-directed immunotherapy against MRSA and other bacterial skin infections.