Does the shape of lipid A determine the interaction of LPS with Toll-like receptors?

Lipopolysaccharide (LPS) triggers the activation of the immune system through the induction of cytokine release. Although it was assumed initially that LPS molecules from different bacteria are similar, recent evidence suggests that structural and functional differences between LPS species are the rule rather than the exception. It has been proposed that the shape of the lipid A component determines the bioactivity of LPS, with lipid A that adopts a conical conformation being more active than lipid A that adopts a cylindrical shape. The mechanism linking the molecular conformation with the biological activity of LPS has not been elucidated. We propose that LPS with a conical shape (e.g. from Escherichia coli) induces cytokine production through Toll-like receptor 4 (TLR4), whereas more cylindrical LPS (e.g. from Porphyromonas gingivalis) induces expression of a different set of cytokines through TLR2. Strictly cylindrical LPS molecules (e.g. the lipid A precursor Ia or from Rhodobacter sphaeroides) have antagonistic properties at the level of TLRs.