Targeting the inflammasome: clearance of Methicillin-Resistant Staphylococcus aureus in skin and soft tissue infections (162.14)

Abstract

We reported an endogenously derived inflammasome activating lipopeptide (1-peptidyl-2-arachidonoyl-3-stearoyl glyceride) with the amino acid sequence for the peptide being acALYDKGYTSKEQKDCVGI (acALY18) and determined that the peptide alone was responsible for the biological activity. Inflammasomes are important for the activation of the innate immune response by detection of danger signals in response to pathogen infection and sterile injury. The inflammasomes modulate the activation of IL-1β and IL-18, by controlling the activation of caspase-1 that cleaves these cytokines for secretion. In fibroblasts, the activation of the inflammasome mediated signaling events by acALY18 was inhibited by Z-YVAD(OMe)-FMK (caspase-1 inactivator) and secretion of IL-1β and IL-18 was abolished. Inflammasome activation in primary human fibroblasts suggests that acALY-18 could be prophylactically useful for the prevention of hospital-acquired infections. Therefore, we conducted a pilot study consisting of two cohorts of 30 mice each infected with MRSA +/- 100 μg/Kg acALY18. In both cohorts, acALY18 reduced the pathogen load in the tissues resulting in smaller lesions and an increased healing rate whereas the untreated mice had much larger lesions with a thick, purulent exudate and no signs of healing. This data suggests that in vivo administration of acALY-18 could induce innate immune responses that would be prophylactically useful for the prevention of hospital-acquired infections.