Toll-like receptors (TLRs) are type-I transmembrane proteins with extracellular leucine-rich repeat (LRR) motifs and an intracellular Toll/interleukin-1R (TIR) domain.
TLR genes are restricted to eumetazoans and probably originated at the dawn of animal evolution more than 700 million years ago.
With rare exceptions, both TLR and nuclear factor-kappaB (NF-κB) genes are found in sequenced animal genomes, pointing to the ancient origin of the TLR–NF-κB signalling module.
Early diversification of TLR structures resulted in two forms of the protein: multiple cysteine cluster TLRs found mostly in protostomes and single cysteine cluster TLRs found mostly in deuterostomes.
Three distinct functions of TLRs have been identified: TLRs are essential during host immune responses through NF-κB signalling in insects and vertebrates; they contribute to normal patterning and organogenesis during development through NF-κB signalling in insects; and they contribute to cell adhesion during embryonic development, apparently independently of NF-κB activation in both insects and nematodes.
The lack of functional information on TLRs in several lineages such as lophotrocozoans and cnidarians precludes the drawing of a robust evolutionary scenario for the emergence of TLR-mediated immunity or the ancestral function of TLRs. However, two hypotheses can explain the observed similarities and differences in TLR-mediated immunity in vertebrates and insects: an ancient origin of TLR-mediated immunity in the bilaterian ancestor followed by a substantial diversification along the lineages; or a convergent evolution based on the independent recruitment of TLRs to mediate immunity in deuterostomes and insects.
The recurrent use of similar protein modules (the TIR domain and LRR motifs) and signalling pathways (NF-κB) in the immune response is observed in phylogenetically distant lineages.
Future challenges include analysing TLR function in invertebrate deuterostomes, lophochotrozoan and cnidarian model organisms, and further dissection of the NF-κB-independent role of TLRs during development.
The Toll receptor was initially identified in Drosophila melanogaster for its role in embryonic development. Subsequently, D. melanogaster Toll and mammalian Toll-like receptors (TLRs) have been recognized as key regulators of immune responses. After ten years of intense research on TLRs and the recent accumulation of genomic and functional data in diverse organisms, we review the distribution and functions of TLRs in the animal kingdom. We provide an evolutionary perspective on TLRs, which sheds light on their origin at the dawn of animal evolution and suggests that different TLRs might have been co-opted independently during animal evolution to mediate analogous immune functions.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Anderson, K. V., Jurgens, G. & Nusslein-Volhard, C. Establishment of dorsal–ventral polarity in the Drosophila embryo: genetic studies on the role of the Toll gene product. Cell 42, 779–789 (1985). This paper describes the initial characterization of Drosophila Toll alleles.
Gerttula, S., Jin, Y. S. & Anderson, K. V. Zygotic expression and activity of the Drosophila Toll gene, a gene required maternally for embryonic dorsal–ventral pattern formation. Genetics 119, 123–133 (1988).
Eldon, E. et al. The Drosophila 18 wheeler is required for morphogenesis and has striking similarities to Toll. Development 120, 885–899 (1994).
Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).
Pasare, C. & Medzhitov, R. Toll-like receptors: linking innate and adaptive immunity. Adv. Exp. Med. Biol. 560, 11–18 (2005).
Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J. & Hoffmann, J. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983 (1996). This paper describes the first implication of a TLR in host defence.
Buchanan, S. G. & Gay, N. J. Structural and functional diversity in the leucine-rich repeat family of proteins. Prog. Biophys. Mol. Biol. 65, 1–44 (1996).
Kobe, B. & Kajava, A. V. The leucine-rich repeat as a protein recognition motif. Curr. Opin. Struct. Biol. 11, 725–732 (2001).
Bell, J. K. et al. The molecular structure of the Toll-like receptor 3 ligand-binding domain. Proc. Natl Acad. Sci. USA 102, 10976–10980 (2005).
Choe, J., Kelker, M. S. & Wilson, I. A. Crystal structure of human Toll-like receptor 3 (TLR3) ectodomain. Science 309, 581–585 (2005).
Weber, A. N. et al. Binding of the Drosophila cytokine Spätzle to Toll is direct and establishes signaling. Nature Immunol. 4, 794–800 (2003).
Mizel, S. B., West, A. P. & Hantgan, R. R. Identification of a sequence in human Toll-like receptor 5 required for the binding of Gram-negative flagellin. J. Biol. Chem. 278, 23624–23629 (2003).
Andersen-Nissen, E., Smith, K. D., Bonneau, R., Strong, R. K. & Aderem, A. A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin. J. Exp. Med. 204, 393–403 (2007).
Jin, M. S. et al. Crystal structure of the TLR1–TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130, 1071–1082 (2007).
Cornelie, S. et al. Direct evidence that Toll-like receptor 9 (TLR9) functionally binds plasmid DNA by specific cytosine–phosphate–guanine motif recognition. J. Biol. Chem. 279, 15124–15129 (2004).
Rutz, M. et al. Toll-like receptor 9 binds single-stranded CpG–DNA in a sequence- and pH-dependent manner. Eur. J. Immunol. 34, 2541–2550 (2004).
Kufer, T. A., Fritz, J. H. & Philpott, D. J. NACHT-LRR proteins (NLRs) in bacterial infection and immunity. Trends Microbiol. 13, 381–388 (2005).
Martinon, F. & Tschopp, J. NLRs join TLRs as innate sensors of pathogens. Trends Immunol. 26, 447–454 (2005).
DeYoung, B. J. & Innes, R. W. Plant NBS-LRR proteins in pathogen sensing and host defense. Nature Immunol. 7, 1243–1249 (2006).
Werts, C., Girardin, S. E. & Philpott, D. J. TIR, CARD and PYRIN: three domains for an antimicrobial triad. Cell Death Differ. 13, 798–815 (2006).
Bowie, A. et al. A46R and A52R from vaccinia virus are antagonists of host IL-1 and Toll-like receptor signaling. Proc. Natl Acad. Sci. USA 97, 10162–10167 (2000).
Belvin, M. P. & Anderson, K. V. A conserved signaling pathway: the Drosophila Toll–Dorsal pathway. Annu. Rev. Cell Dev. Biol. 12, 393–416 (1996).
Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997). This paper shows the first link between TLR- and NF-κB-mediated immune responses in vertebrates.
Xu, Y. et al. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 408, 111–115 (2000).
Boraschi, D. & Tagliabue, A. The interleukin-1 receptor family. Vitam. Horm. 74, 229–254 (2006).
Miller, D. J. et al. The innate immune repertoire in cnidaria — ancestral complexity and stochastic gene loss. Genome Biol. 8, R59 (2007).
Ausubel, F. M. Are innate immune signaling pathways in plants and animals conserved? Nature Immunol. 6, 973–979 (2005).
Philippe, H., Lartillot, N. & Brinkmann, H. Multigene analyses of bilaterian animals corroborate the monophyly of Ecdysozoa, Lophotrochozoa, and Protostomia. Mol. Biol. Evol. 22, 1246–1253 (2005).
Putnam, N. H. et al. Sea anemone genome reveals ancestral eumetazoan gene repertoire and genomic organization. Science 317, 86–94 (2007).
Sullivan, J. C., Kalaitzidis, D., Gilmore, T. D. & Finnerty, J. R. Rel homology domain-containing transcription factors in the cnidarian Nematostella vectensis. Dev. Genes Evol. 217, 63–72 (2007). This paper describes the initial identification of TLR and NF-κB genes in a cnidarian.
Zheng, L., Zhang, L., Lin, H., McIntosh, M. T. & Malacrida, A. R. Toll-like receptors in invertebrate innate immunity. Invertebrate Survival Journal 2, 105–113 (2005).
Wiens, M. et al. Innate immune defense of the sponge Suberites domuncula against bacteria involves a MyD88-dependent signaling pathway. Induction of a perforin-like molecule. J. Biol. Chem. 280, 27949–27959 (2005).
Wiens, M. et al. Toll-like receptors are part of the innate immune defense system of sponges (demospongiae: Porifera). Mol. Biol. Evol. 24, 792–804 (2007).
Beutler, B. Innate immunity: an overview. Mol. Immunol. 40, 845–859 (2004).
Imler, J. L. & Zheng, L. Biology of Toll receptors: lessons from insects and mammals. J. Leukoc. Biol. 75, 18–26 (2004).
Luo, C. & Zheng, L. Independent evolution of Toll and related genes in insects and mammals. Immunogenetics 51, 92–98 (2000).
Friedman, R. & Hughes, A. L. Molecular evolution of the NF-κB signaling system. Immunogenetics 53, 964–974 (2002).
Kanzok, S. M. et al. Origin of Toll-like receptor-mediated innate immunity. J. Mol. Evol. 58, 442–448 (2004).
Roach, J. C. et al. The evolution of vertebrate Toll-like receptors. Proc. Natl Acad. Sci. USA 102, 9577–9582 (2005). References 35 to 39 provide phylogenetic data supporting the independent evolution of TLRs in different phyla.
Anderson, K. V. & Nüsslein-Volhard, C. in Pattern Formation: A Primer in Developmental Biology (eds Malacinsky, G. M. & Bryant, S.) 269–289 (MacMillian Publishers Ltd, New York, 1984).
Moussian, B. & Roth, S. Dorsoventral axis formation in the Drosophila embryo — shaping and transducing a morphogen gradient. Curr. Biol. 15, R887–R899 (2005).
Roth, S. The origin of dorsoventral polarity in Drosophila. Phil. Trans. R. Soc. Lond. 358, 1317–1329 (2003).
Letsou, A., Alexander, S., Orth, K. & Wasserman, S. A. Genetic and molecular characterization of tube, a Drosophila gene maternally required for embryonic dorso-ventral polarity. Proc. Natl Acad. Sci. USA 88, 810–814 (1991).
Halfon, M. S., Hashimoto, C. & Keshishian, H. The Drosophila Toll gene functions zygotically and is necessary for proper motoneuron and muscle development. Dev. Biol. 169, 151–167 (1995).
Halfon, M. S. & Keshishian, H. The Toll pathway is required in the epidermis for muscle development in the Drosophila embryo. Dev. Biol. 199, 164–174 (1998).
Rose, D. et al. Toll, a muscle cell surface molecule, locally inhibits synaptic initiation of the RP3 motoneuron growth cone in Drosophila. Development 124, 1561–1571 (1997).
Wang, J. et al. Expression, regulation, and requirement of the Toll transmembrane protein during dorsal vessel formation in Drosophila melanogaster. Mol. Cell Biol. 25, 4200–4210 (2005).
Keith, J. & Gay, N. The Drosophila membrane receptor Toll can function to promote cellular adhesion. EMBO J. 9, 4299–4306 (1990).
Tauszig-Delamasure, S., Bilak, H., Capovilla, M., Hoffmann, J. A. & Imler, J. L. Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections. Nature Immunol. 3, 91–97 (2002).
Rutschmann, S., Kilinc, A. & Ferrandon, D. Cutting edge: the Toll pathway is required for resistance to Gram-positive bacterial infections in Drosophila. J. Immunol. 168, 1542–1546 (2002).
De Gregorio, E., Spellman, P. T., Tzou, P., Rubin, G. M. & Lemaitre, B. The Toll and Imd pathways are the major regulators of the immune response in Drosophila. EMBO J. 21, 2568–2579 (2002).
Lemaitre, B. & Hoffmann, J. The host defense of Drosophila melanogaster. Annu. Rev. Immunol. 25, 697–743 (2007).
Ferrandon, D., Imler, J. L. & Hoffmann, J. A. Sensing infection in Drosophila: Toll and beyond. Semin. Immunol. 16, 43–53 (2004).
Qiu, P., Pan, P. C. & Govind, S. A role for the Drosophila Toll/Cactus pathway in larval hematopoiesis. Development 125, 1909–1920 (1998).
Sorrentino, R. P., Carton, Y. & Govind, S. Cellular immune response to parasite infection in the Drosophila lymph gland is developmentally regulated. Dev. Biol. 243, 65–80 (2002).
Kambris, Z., Hoffmann, J. A., Imler, J. L. & Capovilla, M. Tissue and stage-specific expression of the Tolls in Drosophila embryos. Gene Expr. Patterns 2, 311–317 (2002).
Kolesnikov, T. & Beckendorf, S. K. 18 wheeler regulates apical constriction of salivary gland cells via the Rho–GTPase-signaling pathway. Dev. Biol. 307, 53–61 (2007).
Kleve, C. D., Siler, D. A., Syed, S. K. & Eldon, E. D. Expression of 18 wheeler in the follicle cell epithelium affects cell migration and egg morphology in Drosophila. Dev. Dyn. 235, 1953–1961 (2006).
Seppo, A., Matani, P., Sharrow, M. & Tiemeyer, M. Induction of neuron-specific glycosylation by Tollo/Toll8, a Drosophila Toll-like receptor expressed in non-neural cells. Development 130, 1439–1448 (2003).
Aoki, K. et al. Dynamic developmental elaboration of N-linked glycan complexity in the Drosophila melanogaster embryo. J. Biol. Chem. 282, 9127–9142 (2007).
Tauszig, S., Jouanguy, E., Hoffmann, J. A. & Imler, J. L. Toll-related receptors and the control of antimicrobial peptide expression in Drosophila. Proc. Natl Acad. Sci. USA 97, 10520–10525 (2000).
Lazzaro, B. P., Sackton, T. B. & Clark, A. G. Genetic variation in Drosophila melanogaster resistance to infection: a comparison across bacteria. Genetics 174, 1539–1554 (2006).
Luo, C., Shen, B., Manley, J. L. & Zheng, L. Tehao functions in the Toll pathway in Drosophila melanogaster: possible roles in development and innate immunity. Insect Mol. Biol. 10, 457–464 (2001).
Ooi, J. Y., Yagi, Y., Hu, X. & Ip, Y. T. The Drosophila Toll9 activates a constitutive antimicrobial defense. EMBO Rep. 3, 82–87 (2002).
Rubin, G. M. et al. Comparative genomics of the eukaryotes. Science 287, 2204–2215 (2000).
Christophides, G. K. et al. Immunity-related genes and gene families in Anopheles gambiae. Science 298, 159–165 (2002).
Evans, J. D. et al. Immune pathways and defence mechanisms in honey bees Apis mellifera. Insect Mol. Biol. 15, 645–656 (2006).
Cheng, T. C. et al. Identification and analysis of Toll-related genes in the domesticated silkworm, Bombyx mori. Dev. Comp. Immunol. (2007).
Waterhouse, R. M. et al. Evolutionary dynamics of immune-related genes and pathways in disease-vector mosquitoes. Science 316, 1738–1743 (2007).
Zou, Z. et al. Comparative genomic analysis of the Tribolium immune system. Genome Biol. 8, R177 (2007).
Chintapalli, V. R., Wang, J. & Dow, J. A. Using FlyAtlas to identify better Drosophila melanogaster models of human disease. Nature Genet. 39, 715–720 (2007).
Shin, S. W., Bian, G. & Raikhel, A. S. A Toll receptor and a cytokine, Toll5A and Spz1C, are involved in Toll antifungal immune signaling in the mosquito Aedes aegypti. J. Biol. Chem. 281, 39388–39395 (2006). This paper shows a similar role for TLRs in the antifungal immune response in Diptera.
Pujol, N. et al. A reverse genetic analysis of components of the Toll signaling pathway in Caenorhabditis elegans. Curr. Biol. 11, 809–821 (2001). This paper presents a functional analysis of the unique C. elegans TLR.
Tenor, J. L. & Aballay, A. A conserved Toll-like receptor is required for Caenorhabditis elegans innate immunity. EMBO Rep. 9, 103–109 (2008).
Chuang, C. F. & Bargmann, C. I. A Toll-interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling. Genes Dev. 19, 270–281 (2005).
Couillault, C. et al. TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nature Immunol. 5, 488–494 (2004).
Liberati, N. T. et al. Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response. Proc. Natl Acad. Sci. USA 101, 6593–6598 (2004).
Beutler, B. et al. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu. Rev. Immunol. 24, 353–389 (2006).
O'Neill, L. A. & Bowie, A. G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nature Rev. Immunol. 7, 353–364 (2007).
Kawai, T. & Akira, S. TLR signaling. Semin. Immunol. 19, 24–32 (2007).
Takeda, K. & Akira, S. Toll-like receptors in innate immunity. Int. Immunol. 17, 1–14 (2005).
Pasare, C. & Medzhitov, R. Toll-like receptors: linking innate and adaptive immunity. Microbes Infect. 6, 1382–1387 (2004).
Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nature Immunol. 5, 987–995 (2004).
Sutmuller, R. P., Morgan, M. E., Netea, M. G., Grauer, O. & Adema, G. J. Toll-like receptors on regulatory T cells: expanding immune regulation. Trends Immunol. 27, 387–393 (2006).
Ma, Y. et al. Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis. J. Cell Biol. 175, 209–215 (2006).
Cameron, J. S. et al. Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals. J. Neurosci. 27, 13033–13041 (2007).
Rolls, A. et al. Toll-like receptors modulate adult hippocampal neurogenesis. Nature Cell Biol. 9, 1081–1088 (2007). References 85 to 87 report the involvement of mouse TLRs in neurogenesis.
Cook, D. N., Pisetsky, D. S. & Schwartz, D. A. Toll-like receptors in the pathogenesis of human disease. Nature Immunol. 5, 975–979 (2004).
Bochud, P. Y., Bochud, M., Telenti, A. & Calandra, T. Innate immunogenetics: a tool for exploring new frontiers of host defence. Lancet Infect. Dis. 7, 531–542 (2007).
Picard, C. et al. Pyogenic bacterial infections in humans with IRAK4 deficiency. Science 299, 2076–2079 (2003).
Casrouge, A. et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 314, 308–312 (2006).
Zhang, S.-Y. et al. TLR3 Deficiency in patients with herpes simplex encephalitis. Science 317, 1522 (2007).
Ku, C. L. et al. Inherited disorders of human Toll-like receptor signaling: immunological implications. Immunol. Rev. 203, 10–20 (2005).
Berczi, I., Bertok, L. & Bereznai, T. Comparative studies on the toxicity of Escherichia coli lipopolysaccharide endotoxin in various animal species. Can. J. Microbiol. 12, 1070–1071 (1966).
Iliev, D. B., Roach, J. C., Mackenzie, S., Planas, J. V. & Goetz, F. W. Endotoxin recognition: in fish or not in fish? FEBS Lett. 579, 6519–6528 (2005).
Ishii, A. et al. Lamprey TLRs with properties distinct from those of the variable lymphocyte receptors. J. Immunol. 178, 397–406 (2007).
van der Sar, A. M. et al. MyD88 innate immune function in a zebrafish embryo infection model. Infect. Immun. 74, 2436–2441 (2006).
Rast, J. P., Smith, L. C., Loza-Coll., M., Hibino, T. & Litman, G. W. Genomic insights into the immune system of the sea urchin. Science 314, 952–956 (2006).
Hibino, T. et al. The immune gene repertoire encoded in the purple sea urchin genome. Dev. Biol. 300, 349–365 (2006). References 98 and 99 describe and discuss the striking amplification of TLR genes in the sea urchin genome.
Pancer, Z. & Cooper, M. D. The evolution of adaptive immunity. Annu. Rev. Immunol. 24, 497–518 (2006).
Bourlat, S. J. et al. Deuterostome phylogeny reveals monophyletic chordates and the new phylum Xenoturbellida. Nature 444, 85–88 (2006).
Azumi, K. et al. Genomic analysis of immunity in a urochordate and the emergence of the vertebrate immune system: 'waiting for Godot'. Immunogenetics 55, 570–581 (2003).
Khalturin, K., Panzer, Z., Cooper, M. D. & Bosch, T. C. Recognition strategies in the innate immune system of ancestral chordates. Mol. Immunol. 41, 1077–1087 (2004).
Hughes, A. L. Protein phylogenies provide evidence of a radical discontinuity between arthropod and vertebrate immune systems. Immunogenetics 47, 283–296 (1998).
Boman, H. G. & Hultmark, D. Cell-free immunity in insects. Annu. Rev. Microbiol. 41, 103–126 (1987).
Hultmark, D. Insect lysozymes. EXS 75, 87–102 (1996).
Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).
Hoshino, K. et al. Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 162, 3749–3752 (1999).
Qureshi, S. T. et al. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (TLR4). J. Exp. Med. 189, 615–625 (1999). References 107 to 109 are the first reports of the essential role of TLRs in vertebrate immunity.
Takeuchi, O. et al. Cutting edge: preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a Toll-like receptor 2- and MyD88-dependent signaling pathway. J. Immunol. 164, 554–557 (2000).
Takeuchi, O. et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 13, 933–940 (2001).
Takeuchi, O. et al. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169, 10–14 (2002).
Hayashi, F. et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099–1103. (2001).
Zhang, D. et al. A Toll-like receptor that prevents infection by uropathogenic bacteria. Science 303, 1522–1526 (2004).
Yarovinsky, F. et al. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308, 1626–1629 (2005).
Alexopoulou, L., Holt, A. C., Medzhitov, R. & Flavell, R. A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738. (2001).
Hemmi, H. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nature Immunol. 3, 196–200 (2002).
Heil, F. et al. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur. J. Immunol. 33, 2987–2997 (2003).
Hornung, V. et al. Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nature Med. 11, 263–270 (2005).
Jurk, M. et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nature Immunol. 3, 499 (2002).
Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526–1529 (2004).
Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).
Lund, J., Sato, A., Akira, S., Medzhitov, R. & Iwasaki, A. Toll-like receptor 9-mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells. J. Exp. Med. 198, 513–520 (2003).
Coban, C. et al. Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J. Exp. Med. 201, 19–25 (2005).
Goodson, M. S. et al. Identifying components of the NF-κB pathway in the beneficial Euprymna scolopes–Vibrio fischeri light organ symbiosis. Appl. Environ. Microbiol. 71, 6934–6946 (2005).
Qiu, L., Song, L., Xu, W., Ni, D. & Yu, Y. Molecular cloning and expression of a Toll receptor gene homologue from Zhikong Scallop, Chlamys farreri. Fish Shellfish Immunol. 22, 451–466 (2007).
Matsuo, K., Yoshida, H. & Shimizu, T. Differential expression of caudal and dorsal genes in the teloblast lineages of the oligochaete annelid Tubifex tubifex. Dev. Genes Evol. 215, 238–247 (2005).
Goldstein, B., Leviten, M. W. & Weisblat, D. A. Dorsal and snail homologs in leech development. Dev. Genes Evol. 211, 329–337 (2001).
Carty, M. et al. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nature Immunol. 7, 1074–1081 (2006).
Adoutte, A. et al. The new animal phylogeny: reliability and implications. Proc. Natl Acad. Sci. USA 97, 4453–4456 (2000).
We are grateful to B. Prud'homme, J. Bangham, J. Casanova and colleagues at the Centre de Génétique Moléculaire for discussions and insights on our manuscript. We apologise to the many authors whose work has not been directly cited because of space limitation.
Heterotrophic multicellular organisms (that is, animals).
Animal taxon including all animal species in which the blastopore forms the anus.
The clade comprising all major animal groups except sponges (that is, cnidarians to vertebrates).
Animal taxon including all animal species in which the blastopore forms the mouth.
Animals with bilateral symmetry.
- Fat body
The functional equivalent, in insects, of the mammalian liver.
- Avoidance behaviour
C. elegans worms that are fed on bacterial lawn in experimental conditions have the capacity to discriminate between bacterial species and avoid pathogenic bacteria such as Serratia marcescens, while being attracted by non-pathogenic species such as Escherichia coli.
- Paneth cells
Specialized epithelial cells of the small intestine, which provide host defence against microorganisms.
- Endotoxin shock
A medical condition that is caused by decreased tissue perfusion and oxygen delivery as a result of lipopolysaccharide contamination of the blood stream.
A synthetic molecule used to modify gene expression.
Circulating cells that are present in the body cavity (coelome) of sea urchins and other invertebrates.
- Adaptive immune system
The long-lasting host defence response to infection, which is acquired during the life of the host.
The phylum of animals that is defined by the presence of a notochord.
- Complement system
A complex system of proteins that interact in a proteolytic cascade, leading to pathogen clearance in the serum.
- Innate immune response
The first line of defence against invading organisms, which is inherited.
A taxonomic group of organisms comprising a single common ancestor and all the descendants of that ancestor.
- Convergent evolution
The process whereby organisms that are not closely related (not monophyletic) independently evolve similar traits as a result of having to adapt to similar environments or ecological niches.
About this article
Cite this article
Leulier, F., Lemaitre, B. Toll-like receptors — taking an evolutionary approach. Nat Rev Genet 9, 165–178 (2008). https://doi.org/10.1038/nrg2303
Proceedings of the Royal Society B: Biological Sciences (2021)
Frontiers in Immunology (2021)
The immune system of sturgeons and paddlefish (Acipenseriformes): a review with new data from a chromosome‐scale sturgeon genome
Reviews in Aquaculture (2021)
Brain, Behavior, and Immunity (2021)