Peptidoglycan acts as a Gram-positive endotoxin (P4035)

Abstract We proposed that peptidoglycan (PGN) contributes to the systemic inflammation and sepsis accompanying Gram-positive infections. However responses are dependent on pre-existing IgG recognizing peptidoglycan and capable of engaging Fcgamma receptors. Mice lack these antibodies and hence respond weakly to in vivo PGN challenges. Non-human primates possess anti-PGN IgG and have been a useful and informative model for sepsis, We challenged 4 baboons with varying doses (7-48 mg/Kg) of PGN and noted: vascular leakage, increased circulating proinflammatory cytokines, increased activation of neutrophils and platelets, expression of tissue factor on monocytes, massive consumption of clotting factors and complement proteins, and microthrombosis-induced kidney failure. The severity of the outcome correlated with the pre-existing titer of anti-PGN antibodies such that animals with a higher titer had a poorer outcome. The pathological features induced by the sterile PGN infusion greatly resemble the pathological features induced by infusion of live bacteria from which the PGN was generated. The data support our hypothesis that PGN and anti-PGN antibodies are a major contributor to Gram-positive sepsis.