Introduction

Sensing of microbial pathogens is essential for mounting a strong antibacterial immune defense and for survival of the host. Because of molecular heterogeneity and rapid evolution of pathogens, a recognition strategy by host cells has evolved that is based on detection of conserved molecular patterns that are unique to microbes and highly conserved among entire classes of pathogens. During infection, cells of the innate immune system recognize conserved molecular structures of pathogens either in the context of the bacterial membrane or when released in circulation [1, 2]. Recognition of certain bacterial structures, e.g., lipopolysaccharide (LPS) and lipoarabinomannan (LAM), is initiated by high affinity co-receptors, e.g., CD14 [3-7] that bind various pathogen products and ultimately present them to Toll-like receptors (TLRs) that trigger signal transduction. TLRs are evolutionarily conserved, non-clonally distributed signaling receptors expressed predominantly on monocytes, macrophages, and neutrophils [1, 2, 8, 9]. All 10 human TLRs express an extracellular leucine-rich region, a transmembrane portion, and a cytoplasmic tail with a conserved "Toll-IL-1 resistance" (TIR) domain that is essential for mediating signal transduction of both TLRs and the IL-1 receptor (IL-1R) [8-10]. A lack of LPS sensitivity in TLR4-mutant or knockout (KO) mice [10-14], coupled with a gain of LPS responsiveness upon TLR4 expression in LPS-unresponsive cell lines [15-17], point to TLR4 as the primary signal transducing receptor for LPS. In addition to its ability to transduce intracellular signals that enable responsiveness to most lipopolysaccharide (LPS) species, TLR4 also responds to structurally unrelated microbial structures, e.g., the fusion (F) protein of respiratory syncytial virus [18], Chlamydial heat shock protein (HSP) 60 [19], and pneumolysin [20], as well as paclitaxel (TAXOL™) [21], a plant-derived diterpenoid whose specificity for TLR4 is restricted to murine cells. In addition, TLR4 has been reported to respond to endogenous agonists (reviewed in [22]) including heat shock proteins 60 and 70, fibrinogen, fibronectin, surfactant protein A, and murine P-defensin 2. This suggests the possibility that such endogenous agonists may play critical roles in alerting the

Toll-like Receptors in Inflammation, edited by Luke A.J. O'Neill and Elizabeth Brint © 2006 Birkhauser Verlag Basel/Switzerland host to "danger" since many are associated with cellular damage. Thus, TLR4 represents, perhaps, the most versatile of the all TLRs. TLR2 enables responses to components of Gram-positive bacteria (e.g., lipoteichoic acid (LTA) and lipopeptides) [23, 24], mycobacterium (e.g., LAM) [24, 25], mycoplasma lipopeptides [24-26], and HSP70 [27, 28]. TLR1 and TLR6 do not elicit signaling on their own, but are required for TLR2-mediated responses [29, 30]. TLR3 and TLR5 agonists include viral double-stranded RNA and many species of flagellin, respectively [31, 32], while TLR9 responds to unmethylated CpG motifs found in bacterial DNA [33]. Antiviral imidazoquinoline compounds, imiquimod and resiquimod, activate cells via human TLR7 and TLR8 [34, 35], respectively, and murine TLR7 is capable of recognizing another synthetic compound, loxoribine [36]. Because of structural similarities of both imidazoqinoline and loxoribine to guanosine nucleoside, TLR7 and TLR9 were predicted to recognize a nucleic acid-like structure of viruses. This has recently proven to be the case, as TLR7 and TLR8 recognize quanosine- or uridine-rich single-stranded RNA from human immunodeficiency virus, vesicular stomatitis virus, and influenza virus [37]. Thus, TLRs 1, 2, 4, 5, and 6 are more involved in recognition of bacterial products and, possibly, some host proteins, whereas TLRs 3, 7, 8, and 9 detect viral or bacterial nucleic acids preferentially (Fig. 1). Interestingly, whereas TLR4 and TLR5 recognize their ligands at the cell surface, TLR2 is expressed on the cell membrane and is recruited to the macrophage phagosomes after exposure to zymosan. In contrast, TLR3, TLR7, and TLR9 agonist sensing requires endosomal maturation and appears to occur in endosomes (reviewed in [38]; Fig. 1). Thus, TLRs discriminate diverse microbial and viral structures, as well as endogenous eukaryotic proteins released after cell damage as a consequence of wounding and/or infection. This elicits the host defense against infection and enables responses to "danger signals" associated with cellular damage [21].

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