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

According 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 4′ 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 pro-inflammatory signaling by human TLR4 occur only when lipid A has both phosphates and is hexaacyl, with two secondary acyl chains. What might bacteria derive from producing this type of lipid A, and what do animals gain from recognizing it? A survey of diverse lipid A structures found that the best-recognized configuration is produced by most of the aerobic or facultatively anaerobic Gram-negative bacteria that can live in the gastrointestinal and upper respiratory tracts. We hypothesize that the CD14–MD-2–TLR4 mechanism evolved to recognize not just pathogens, but also many of the commensals (normal flora) and colonizers that can inhabit the body's most vulnerable surfaces. Producing this lipid A structure seems to favor bacterial persistence on host mucosae, whereas recognizing it allows the host to kill invading bacteria within subepithelial tissues and prevent dissemination. A conserved host lipase can then limit the inflammatory response by removing a key feature of the lipid A signal, the secondary acyl chains.