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van Mourik et al. (1) recently deduced that the mixed lipid A of Campylobacter jejuni lipooligosaccharide, containing both glucosamine and diaminoglucose as backbone sugars, induces less cellular activation through the TLR4-MD2 complex than classical enterobacterial lipid A (containing glucosamine alone) and endows this bacterium with greater resistance to antimicrobial peptides, due to the presence of a greater proportion of amide-linked fatty acids in the former lipid A. This is consistent with our previous hypothesis (2) that the presence of three rather than two amide-liked fatty acids in the predominant C. jejuni lipid A species (3) influences a range of observed biological activities (4).
However, van Mourik et al. (1) speculated that a reduced flexibility of the amide-linked acyl chains in C. jejuni lipid A would affect interaction with the TLR4-MD2 complex and thus influence cellular activation. Our previous studies have shown that the phase transition at 37° C of C. jejuni compared to enterobacterial lipopolysaccharide is lower, reflecting the presence of longer non-hydroxylated acyl chains (4), but the three-dimensional supramolecular conformation of lipid A, which is not only influenced by amide linkage of acyl chains, but also by the phosphate and polar head group substitution of the lipid A backbone, as well as by acyl chain distribution and lengths, can be correlated with the lower biological activities of C. jejuni lipid A (5). Moreover, as demonstrated recently (6), C. jejuni susceptibility to antimicrobial peptides can be influenced by phosphoethanolamine substitution in lipid A. Thus, the role of other structural features of diaminoglucose-containing lipid A, combined with hydroxyacyl linkage, require further investigation to fully understand their contributory role to lipid A structure-bioactivity relationships.