Molecular heterogeneity and rapid evolution of pathogens led to the development of a recognition strategy that enables the host to sense conserved pathogen-associated molecular patterns (PAMPs) derived from bacteria, viruses, fungi, and protozoa by "pattern-recognition receptors" (PRRs; Medzhitov and Janeway 2000). The non-clonal distribution of PRRs and their ubiquitous expression on various cell types enables a rapid immune response upon encounter with pathogens, providing a first line of host immune defense (Medzhitov and Janeway 2000, 2002; Janeway and Medzhitov 2002). PAMP recognition by PRRs is an ancient mechanism of host immune defense present in plants, zebra fish, crabs, Drosophila, and mammals (Janeway and Medzhitov 2002; Inamori et al. 2004; Meijer et al. 2004). One of the most important families of PRRs, the Toll-like Receptor (TLR) family, was initially identified in Drosophila, where a single protein, Toll, mediates dorsal-ventral partitioning during embryogenesis and anti-fungal immune defense in adult flies (Anderson et al. 1985; Lemaitre et al. 1996). In 1997, Janeway and colleagues reported that overexpression of a constitutively active CD4-TLR4 fusion protein resulted in transcription factor activation, cytokine secretion, and up-regulation of co-stimulatory and accessory molecules (Medzhitov et al. 1997), suggesting that TLR4 triggers innate immune responses. Confirming this conclusion, positional cloning studies led to the identification of mouse tlr4 as the elusive Lps gene responsible for LPS recognition and sensing Gram negative bacteria (Poltorak et al. 1998; Qureshi et al. 1999). To date, 12 mammalian TLRs have been identified and most of their ligand recognition patterns characterized (for a review, see Kaisho and Akira 2006). Concurrently, a complex picture of signal transduction pathways triggered by various TLRs has emerged, with many questions regarding agonist recognition, as well as adapter and kinase utilization, still unanswered. In addition, another family of intracellular PRRs, the nucleotide-binding oligomerization domain (NOD) proteins, NOD1 and NOD2, have been identified as important intracellular sensors of peptidoglycan (PGN)-derived components [D-glutamyl-meso-diaminopimelic acid and muramyl dipeptide (MDP), respectively; Idohara and Nunez 2003; Kawai and Akira 2006]. Although bacterial PGN was initially reported as a TLR2 agonist (Dziarski et al. 2001), lipoprotein and lipoteichoic acid (LTA) contaminants of PGN were the likely source of TLR2 activity, as highly purified PGN does not activate TLR2 (Travassos et al. 2004). Very recently, other non-TLR-mediated intracellular sensors of viral nucleic acids and bacterial flagel-lin have been described (e.g., RIG-I, MDA-5, and Ipaf-1, respectively), adding another host safeguard system against viral invasion (Kato et al. 2006; Miao et al. 2006). This review summarizes current knowledge about TLR structure and functions, mechanisms of TLR signaling, and mutations/polymorphisms within TLRs and IRAK-4 associated with autoimmune and infectious diseases and asthma.
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