Shield as Signal: Lipopolysaccharides and the Evolution of Immunity to Gram-Negative Bacteria

ccording to the innate immunity concept [1], animals defend themselves from microbes by recognizing pathogen-associated molecular patterns. To detect many Gram-negative bacteria, animals use the CD14-MD-2-TLR4 receptor mechanism to recognize the lipid A moiety of the cell wall lipopolysaccharide (LPS). Lipid A is a glucosamine disaccharide that carries phosphates at positions 1 and 49 and usually has four primary (glucosamine-linked) hydroxyacyl chains and one or more secondary acyl chains. Gram-negative bacteria produce numerous variations on this basic structure, yet sensitive LPS recognition and proinflammatory signaling by human TLR4 occur only when lipid A has both phosphates and is hexaacyl, with two secondary acyl chains.