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

2006; Public Library of Science; Volume: 2; Issue: 6 Linguagem: Inglês

10.1371/journal.ppat.0020067

1553-7374

Robert S. Munford, Alan W. Varley,

Vibrio bacteria research studies

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.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 bestrecognized 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. Acylation of Lipid A: Strengthening the Shield?Gram-negative bacteria that inhabit water, soil, plants, or insects display impressive diversity in their lipid A structures (see Table S1).Although the backbone is almost always a bisphosphorylated disaccharide that has three or more primary fatty acyl chains, the secondary acyl chains differ in their number, length, and degree of saturation.In contrast, the lipid A structures produced by most of the aerobic and facultatively anaerobic Gram-negative bacteria that live as human mucosal commensals, colonizers, or pathogens [2] are monotonously similar: they have two phosphates, four primary hydroxyacyl chains (3-hydroxymyrisate or 3hydroxylaurate), and two saturated secondary acyl chains (laurate, myristate, or both); we shall refer to this composition as ''mucosal'' lipid A. Since these bacteria differ in many other ways, the fact that their lipid As are so similar suggests that this structure may confer some advantage.Mucosal secretions contain numerous cationic antimicrobial peptides (CAMPs) [3].As noted by Miller [4] and others, increased resistance to CAMPs and other host molecules may explain why Gram-negative bacteria that colonize mucosae usually make LPS with six or more acyl chains (Figure 1).Although we found no demonstration that this lipid A structure enables commensal bacteria to thrive on mucosal surfaces, the evidence that it does so for colonizers and pathogens is extensive.Having hexaacyl (rather than pentaacyl) lipid A enables Bordetella and Haemophilus species to persist in the respiratory tract [5-7] and Neisseria gonorrhoeae to survive within epithelial cells [8].Pseudomonas aeruginosa lives in water, produces a predominantly pentaacylated LPS, and does not colonize the mucosae of normal humans.When P. aeruginosa colonize the airways of children with cystic fibrosis, however, the bacteria often adapt by producing hexaacylated (and even heptaacylated) lipid A [9]. Mucosal lipid A is also found in intestinal pathogens: Shigella and Salmonella, pathogenic Escherichia coli [10], Aeromonas species, Plesiomonas shigelloides, and Vibrio cholerae O1.In Salmonella and some others, a PhoP/PhoQ-regulated transcriptional program promotes lipid A palmitoylation (heptaacylation) along with other changes that increase resistance to CAMPs [4,11-13].Other mucosal bacteria may also produce lipid A that is more hydrophobic than mucosal lipid A, with longer secondary chains (Campylobacter jejuni) or more of them: heptaacyl (Moraxella) or octaacyl (V.cholerae O139).Those that produce less hydrophobic lipid A seem to be special cases: the pentaacyl LPS of Chlamydia species is found in spore-like elementary bodies, and Helicobacter pylori, with tetraacyl LPS, is adapted to live in the stomach.