The Molecular Basis of Lipid A and Toll-Like Receptor 4 Interactions
In 1989 Charles Janeway proposed the concept of ‘Immune recognition’. He suggested that ‘a critical issue for future study is the analysis of microbial signals that induce second signalling capacity in antigen-presenting cells, and the receptors on antige
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Georgina L. Hold and Clare E. Bryant
12.1
Introduction
In 1989 Charles Janeway proposed the concept of ‘Immune recognition’. He suggested that ‘a critical issue for future study is the analysis of microbial signals that induce second signalling capacity in antigen-presenting cells, and the receptors on antigen presenting cells that detect these microbial signals. . . . I term these receptors pattern recognition receptors (PRRs)’ [1]. From the early 1990s genetic studies in Drosophila and vertebrates led to the identification of the membrane associated Toll and Toll-like receptors (TLRs), the canonical PRRs predicted by Janeway. This was followed by the identification of different families of cytosolic PRRs including Retinoic acid-Inducible Gene-Like Receptors, Nucleotide Oligomerisation Domain-like receptors and Absent in melanoma-like receptors all of which play a role in pathogen recognition. There are ten TLRs encoded in the human genome, which bind directly to conserved structures associated with pathogenic microorganisms. These molecules are sometimes termed pathogen associated molecular patterns (PAMPs). TLR PAMPs can be divided broadly into two groups, microbial lipids such as lipopolysaccharide (LPS) and non-self nucleic acids from bacteria, viruses and other pathogenic microorganisms. Microbial lipids are recognized by TLRs 1, 2, 4 and 6, bacterial flagellin by TLR5, RNA by TLRs 3, 7 and 8 and DNA by TLR9. These PAMPs bind and activate TLRs by promoting the dimerization of two receptor
G.L. Hold Division of Applied Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, UK AB25 2ZD e-mail: [email protected] C.E. Bryant (*) Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, UK CB3 0ES e-mail: [email protected] Y.A. Knirel and M.A. Valvano (eds.), Bacterial Lipopolysaccharides, DOI 10.1007/978-3-7091-0733-1_12, # Springer-Verlag/Wien 2011
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ectodomains causing the cytosolic Toll/IL1 domains (TIR) to associate, creating a signal induced scaffold for the assembly of a post receptor complex [2]. Lipid A was identified in the 1960s as the hydrophobic moiety of lipopolysaccharide (LPS), but its bioactivity was not determined for another 20 years [3]. How the host detects lipid A remained unknown until the discovery of TLRs, specifically TLR4, in the late 1990s [4, 5]. Most Gram-negative bacteria synthesize lipid A molecules resembling those made by Escherichia coli [6]. The characteristic structural features of E. coli lipid A are a 1,4’-bisphosphorylated b-(1 ! 6)linked D-glucosamine disaccharide backbone that is hexaacylated with acyl chains of length C12–C14 which are distributed asymmetrically [7]. This lipid A structure – often referred to as canonical lipid A structure – is required to trigger full TLR4 activation in human cells. More details on lipid A structure, biosynthesis and genetics are discussed in Chaps. 1 and 6. The molecular basis for how E. coli lipid A interacts with TLR4 has been r
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