THE CELL-WALL COMPONENTS PEPTIDOGLYCAN AND LIPOTEICHOIC ACID FROM STAPHYLOCOCCUS-AUREUS ACT IN SYNERGY TO CAUSE SHOCK AND MULTIPLE ORGAN FAILURE

Although the incidence of Gram-positive sepsis has risen strongly, it is unclear how Gram-positive organisms (without endotoxin) initiate se ptic shock. We investigated whether two cell wall components from Stap hylococcus aureus, peptidoglycan (PepG) and lipoteichoic acid (LTA), c an induce the inflammatory response and multiple organ dysfunction syn drome (MODS) associated with septic shock caused by Gram-positive orga nisms. In cultured macrophages, LTA (10 mu g/ml), but not PepG (100 mu g/ml), induces the release of nitric oxide measured as nitrite. PepG, however, caused a 4-fold increase in the production of nitrite elicit ed by LTA. Furthermore, PepG antibodies inhibited the release of nitri te elicited by killed S. aureus. Administration of both PepG (10 mg/kg ; i.v.) and LTA (3 mg/kg; i.v.) in anesthetized rats resulted in the r elease of tumor necrosis factor a: and interferon gamma and MODS, as i ndicated by a decrease in arterial oxygen pressure (lung) and an incre ase in plasma concentrations of bilirubin and alanine aminotransferase (liver), creatinine and urea (kidney), lipase (pancreas), and creatin e kinase (heart or skeletal muscle). There was also the expression of inducible nitric oxide synthase in these organs, circulatory failure, and 50% mortality. These effects were not observed after administratio n of PepG or LTA alone. Even a high dose of LTA (10 mg/kg) causes only circulatory failure but no MODS. Thus, our results demonstrate that t he two bacterial wall components, PepG and LTA, work together to cause systemic inflammation and multiple systems failure associated with Gr am-positive organisms.