Lysostaphin Reduces the Production of Inflammatory Cytokines in Staphylococcus aureus Challenged Mice, and Prevents Systemic Shock

Abstract

Lysostaphin is being developed as a treatment for serious staphylococcal infections. Mice challenged with S. aureus produce inflammatory cytokines including, TNF-� and IL-6, and over-production of these cytokines can lead to shock and contribute to the lethality of staphylococcal infections. Two major components of the staphylococcal cell wall, peptidoglycan and lipoteichoic acid, are known to synergize to induce shock and organ failure in animal models, and we wished to determine whether the rapid lysostaphin-mediated degradation of peptidoglycan during treatment of systemic S. aureus infection could affect shock-associated parameters. We found that lysostaphin treatment of S. aureus-infected mice, which reduces bacteremia and organ infection, also reduced the serum levels of inflammatory cytokines and reversed the symptoms of S. aureus-induced shock. We compared the cytokine response of mice challenged with S. aureus to that of mice challenged with S. aureus and then treated with lysostaphin or nafcillin. Lysostaphin-treated mice, as compared with untreated mice or nafcillin-treated mice, had a blunted cytokine responses to S. aureus challenge. Core body temperature was used as a real time indicator for systemic shock in mice. Mice infected with S. aureus demonstrated a rapid drop in core body temperature, which was reversed by lysostaphin treatment. These studies demonstrated that lysostaphin treatment did not contribute to the induction of shock by rapidly releasing staphylococcal cell wall components, but rather it blunted the inflammatory cytokine response and ameliorated shock related symptoms. Keyword: S. aureus, lysostaphin, shock, cytokine release.