Regulation of Lipopolysaccharide Biologic Activity by Polysaccharide

Summary

Bacterial lipopolysaccharides (LPS) have been implicated as a major contributing factor in the pathogenesis of gram-negative bacterial infections. Biochemical investigations have defined in detail the chemical structure of both the polysaccharide and the lipid A components. In this respect, there is now overwhelming evidence to suggest that the presence of lipid A is essential for the expression of most the multiple pathophysiologic and immunoregulatory properties of LPS. There is, in contrast, significantly less information on the role of the polysaccharide in regulating the biologic expression of the active lipid A component present in native LPS preparations. We have, therefore, performed experiments to examine this question by creating LPS macromolecules which vary significantly in their relative content of lipid A and polysaccharide. One protocol has employed the generation of LPS macromolecular hybrids in which lipid A-rich LPS molecules have been incorporated into native polysaccharide-containing LPS preparations. A second procedure has employed molecular sieve chromatography of detergent-dissociated LPS to generate LPS macromolecules with reduced subunit heterogeneity. The results of these combined studies indicate that the presence of polysaccharide can negatively regulate lipid A activity by two distinct mechanisms. They further support the concept that polysaccharide composition may be as critical a factor in the manifestation of LPS endotoxin activity as is the actual content of lipid A.