Abstract
A 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.
Abstract
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.
Abstract
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 3-hydroxylaurate), 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.
Abstract
Mucosal 

Many other disease-associated Gram-negative bacteria have nonmucosal habitats. Their lipid A moieties differ from the typical mucosal structure by having shorter or longer acyl chains, unsaturated acyl chains, only four or five chains, or only one phosphate (see Table S1 ): Legionella (water habitat, often in free-living amoebae), Burkholderia pseudomallei (soil and water), Yersinia pestis (small rodents, lice), Coxiella burnetti (intracellular, livestock), Leptospira (water, animal urine), and Francisella tularensis (ticks, rabbits, other small animals). These pathogens usually enter vertebrate tissues via insect bites or cuts, within inhaled droplets, or across the conjunctivae. Brucellae Evidence that lipid A structure influences the recognition of intact bacteria by host cells came from mutating enzymes that attach secondary acyl chains to the backbone. Somerville et al. [ 
Other Signals
The host response to LPS also has noninflammatory, immunostimulatory elements. Lipid A analogs that lack the optimal configuration for inducing inflammation may be excellent adjuvants, enhancing acquired immune responses in ways that mimic those induced by LPS itself [57,58]. The mucosal lipid A motif triggers inflammation (and toxicity), whereas adjuvanticity may also follow TLR4-based recognition of lipid A molecules that have only one phosphate and secondary chains of various lengths, numbers, and/or configurations. These structure-function relationships have been exploited to produce analogs that are either LPS antagonists or nontoxic adjuvants.
Other Signals
LPS recognition by CD14-MD-2-TLR4 has received intensive study because it initiates the inflammatory response to so many disease-associated Gram-negative bacteria. Less is known about how animals sense their far more abundant flora of strictly anaerobic Gram-negative bacteria, although doing so may be important for establishing beneficial mutualism between bacteria and host [ 
Accession Numbers
The SwissProt (http://www.ebi.ac.uk/swissprot) primary accession numbers discussed in this paper are AOAH (P28039), CD14 (P08571), MD-2 (Q9Y6Y9), and TLR4 (000206).
Figure 2. AOAH Phylogenetic Tree
Topological algorithm derived using DisplayFam [69] analysis of available sequences. Amino acid similarity/identity to the full-length human sequence is shown (includes both subunits and the pro-peptide). AOAHlike sequences have not been found in fish or insects. The asterisk indicates that AOAH-like enzymatic activity has been demonstrated in one or more cell types. See Table S2 for accession numbers. 

{'paper_id': '2082174', 'title': 'Shield as Signal: Lipopolysaccharides and the Evolution of Immunity to Gram-Negative Bacteria', 's2_url': 'https://api.semanticscholar.org/CorpusID:2082174', 'source': 'S2ORC'}