Synthesis and biological evaluation of lipid A derived from commensal .

The inflammation-inducing properties of lipopolysaccharides (LPS) of Gram-negative bacteria reside in their lipid A moiety. , which is a commensal Gram-negative bacterium, biosynthesises lipid A that is structurally distinct from that of and other enteric bacteria. It is composed of a β1,6-linked glucosamine (GlcN) disaccharide that is only phosphorylated at the anomeric center. The major species of has five fatty acids and the amine of the distal GlcN moiety carries the unusual ()-3-(13-methyltetradecanoyloxy)-1.5-methylhexadecanoic acid. A recent study indicates that the LPS of has anti-viral activity by selective induction of interferon (IFN)-β and is protective in mouse models of vesicular stomatitis virus (VSV) and influenza A. Heterogeneity in the structures of LPS and lipid A and possible contamination with other inflammatory components make it difficult to unambiguously define the immune-modulatory properties of LPS or lipid A. Therefore, we developed a synthetic approach for the preparation of the unusual major lipid A species derived from , which includes a synthetic approach for ()-3-(13-methyltetradecanoyloxy)-1.5-methylhexadecanoic acid by the Wittig olefination to install the terminal isopropyl moiety. The proinflammatory and antiviral responses of synthetic lipid A were investigated in several cell lines and primary human monocytes by examining the production of interleukin (IL)-6 and IFN-β. It was found that does not induce the production of IL-6 and IFN-β but can partially antagonize the production of pro-inflammatory cytokines induced by LPS and lipid A.