Pretreatment with the Gram-positive bacterial cell wall molecule peptidoglycan improves bacterial clearance and decreases inflammation and mortality in mice challenged with Staphylococcus aureus

Objective: To determine whether tolerance and enhancement of innate immune function can be induced by the Gram-positive cell wall component peptidoglycan. Design: Controlled, in vivo laboratory study. Subjects: Male mice, 8-12 wks (C57BL6/J; C3H/HeJ; B6.129Tlr2(tm1kir)/J). Interventions: Mice were given intraperitoneal injections of 1 mg peptidoglycan on two consecutive days, Mice were then challenged with an intravenous injection of live Staphylococcus aureus (1 x 108 colony-forming units) 2 days after the second pretreatment. Measurements and Main Results. Mice pretreated with peptidoglycan had diminished plasma concentrations of tumor necrosis factor-alpha and interferon-gamma in response to the bacterial challenge when compared with untreated controls. Plasma interleukin-10 after bacterial challenge was higher in peptidoglycan-pretreated mice than in controls. Clearance of bacteria after the staphylococcal challenge was improved in mice pretreated with peptidoglycan, and mortality in response to a subsequent Staphylococcus challenge was significantly attenuated. Peptidoglycan pretreatment of mice lacking intact toll-like receptor-4 signaling (C3H/HeJ) or toll-like receptor-2 signaling (toll-like receptor-2 knockouts) had similar effects on plasma cytokine balance, bacterial clearance, and mortality. Conclusions: Exposure to peptidoglycan significantly attenuated inflammation and enhanced bacterial clearance after a subsequent challenge with S. aureus. These results show that exposure to Gram-positive bacterial cell wall components can induce tolerance and enhance innate immune function and neither toll-like receptor-2 nor toll-like receptor-4 are necessary for this phenomenon. Further, although the altered cytokine balance is similar to that seen in septic patients, induced tolerance differs importantly from the clinical scenario of sepsis in that bacterial clearance and survival are improved compared with normal control animals. (Crit Care Med 2008; 36:3067-3073)