The recessive mutation 'Heedless' (hdl) was detected in third-generation N-ethyl-N-nitrosourea-mutated mice that showed defective responses to microbial inducers. Macrophages from Heedless homozygotes signaled by the MyD88-dependent pathway in response to rough lipopolysaccharide (LPS) and lipid A, but not in response to smooth LPS. In addition, the Heedless mutation prevented TRAM-TRIF-dependent signaling in response to all LPS chemotypes. Heedless also abolished macrophage responses to vesicular stomatitis virus and substantially inhibited responses to specific ligands for the Toll-like receptor 2 (TLR2)-TLR6 heterodimer. The Heedless phenotype was positionally ascribed to a premature stop codon in Cd14. Our data suggest that the TLR4-MD-2 complex distinguishes LPS chemotypes, but CD14 nullifies this distinction. Thus, the TLR4-MD-2 complex receptor can function in two separate modes: one in which full signaling occurs and one limited to MyD88-dependent signaling.

CD14 is required for MyD88-independent LPS signaling

The recently chemically synthesized Escherichia coli lipid A and the natural free lipid A of E. coli were compared with respect to their endotoxic activities in the following test systems: lethal toxicity, pyrogenicity, local Shwartzman reactivity, Limulus amoebocyte lysate gelation capacity, tumour necrotizing activity, B cell mitogenicity, induction of prostaglandin synthesis in macrophages, and antigenic specificity. It was found that synthetic and natural free lipid A exhibit identical activities and are indistinguishable in all tests.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1985.tb08798.x

Synthetic and natural Escherichia coli free lipid A express identical endotoxic activities

Innate immune receptors respond to common structural patterns in microbial molecules and are called pattern recognition receptors. Toll-like receptors (TLRs) play critical roles in the innate immune system by recognizing microbial lipids, carbohydrates, nucleic acids, and proteins. Precise definition of the ligand "pattern" of TLRs has been difficult to determine primarily owing to a lack of high-resolution structures. Recently, the structures of several TLR-ligand complexes and the intracellular signaling domains have been determined by X-ray crystallography. This new structural information, combined with extensive biochemical and immunological data accumulated over decades, sheds new light on ligand-recognition and -activation mechanisms. In this review, we summarize the TLR structures and discuss proposed ligand-recognition and -activation mechanisms.

Structural Biology of the Toll-Like Receptor Family

Enzyme-catalyzed synthesis of carbohydrates

Lipopolysaccharides in the cell walls of Gram-negative bacteria elicit toxic as well as potentially beneficial inflammatory responses in animals. It is now reported that tissue toxicity caused by lipopolysaccharides is preferentially reduced by an enzymatic activity in human neutrophils. Acyloxyacyl hydrolysis removes fatty acyl chains that are linked to the hydroxyl groups of 3-hydroxytetradecanoyl residues in the bioactive lipid A moiety of the lipopolysaccharides. Maximal acyloxyacyl hydrolysis reduced lipopolysaccharide tissue toxicity, as measured in the dermal Shwartzman reaction, by a factor of 100 or more. In contrast, the ability of the deacylated lipopolysaccharides to stimulate B lymphocytes to divide was decreased only by a factor of 12. It is suggested that during tissue invasion by Gram-negative bacteria acyloxyacyl hydrolysis may be a defense mechanism that reduces the toxicity of lipopolysaccharides while preserving some of their potentially beneficial inflammatory and immune stimuli.

https://science.sciencemag.org/content/sci/234/4773/203.full.pdf

Detoxification of bacterial lipopolysaccharides (endotoxins) by a human neutrophil enzyme

Synthetic lipid A part structures corresponding structurally to a biosynthetic lipid A disaccharide precursor have been analyzed for endotoxic activity in several systems in vivo and in vitro. It was found that a synthetic beta-1,6-linked D-glucosamine disaccharide, which carries four molar equivalents of (R)-3-hydroxytetradecanoyl residues in positions 2, 3, 2' and 3' and phosphoryl groups in positions 1 and 4' (preparation 406), exhibited lethal toxicity, B lymphocyte mitogenicity, the capacity to engender prostaglandin formation in macrophages and to induce endotoxic tolerance, as well as serological lipid A antigenicity. On a weight basis, preparation 406 was of comparable activity to lipid A precursor and bacterial free lipid A. Preparation 406, like lipid A precursor, lacked, however, the ability to induce the local Shwartzman phenomenon and both preparations were of moderate pyrogenicity. Two further synthetic analogues which contained only one phosphoryl group (preparation 404 at C-4', preparation 405 at C-1) showed comparable or diminished activity depending on the test system employed, except in the capacity to inactivate complement where they exhibited, in contrast to preparation 406, significant activity. The results show that the endotoxic principle of lipopolysaccharides, as postulated previously is embedded in the lipid A component. Our results also suggest initial conclusions on the structural requirements for the expression of endotoxin activities.

Endotoxic properties of chemically synthesized lipid A part structures. Comparison of synthetic lipid A precursor and synthetic analogues with biosynthetic lipid A precursor and free lipid A.

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Endotoxic properties of chemically synthesized lipid A part structures. Comparison of synthetic lipid A precursor and synthetic analogues with biosynthetic lipid A precursor and free lipid A.