Structure of lipid A and cell activation

Abstract

Lipopolysaccharide (LPS) is the principal antigen of Gram-negative bacteria. The free lipid A is derived by mild acid hydrolysis of the LPS. The structures of lipid A from three select sources were compared. The toxic lipid A of Enterobacteriaceae LPS contains 6 fatty acids (C14 or C12) whereas the nontoxic penta-acyl diphosphoryl lipid A derived from the LPS of Rhodobacter sphaeroides (RsDPLA) contains short-chain fatty acids (C10). The nontoxic penta-acyl lipid A from Chlamydia trachomatis contains long-chain fatty acids (C20). This analysis shows that the toxic property of lipid A is determined by the fatty acid composition. Clearly, there is a fine structural requirement for toxicity (and biological activities) of lipid A (including LPS). As an effective antagonist in both human and murine cell lines, RsDPLA is a useful reagent for studying toxic LPS-induced signaling. RsDPLA appears to bind to the putative physiological receptor and does not allow the toxic LPS to bind and initiate signaling. This appears to occur very early at the level of both LBP and CD14. This suggests that RsDPLA may be a useful drug for Gram-negative septic shock.