Abstract
Microbial infection elicits host immune responses through germline-encoded pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are evolutionarily conserved membrane-bound PRRs that recognize a broad spectrum of microbial components. Recent studies have clarified that two classes of cytosolic receptors, retinoic acid-inducible gene I (RIG-I)-like helicases (RLHs) and nucleotide binding oligomerization domain (NOD)-like receptors (NLRs), play important roles in the cytosolic recognition of invading pathogens. After microbial infection, the host utilizes these receptors differentially to mount robust immune responses. This review will describe pathogen recognition by these receptors, signaling pathways, and their in vivo roles in innate antiviral immunity.
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Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001;2:675–680.
Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006;124:783–801.
Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol 2006;7:131–137.
Roach JC, Glusman G, Rowen L, Kaur A, Purcell MK, Smith KD, et al. The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci U S A 2005;102:9577–9582.
Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996;86:973–983.
Pujol N, Link EM, Liu LX, Kurz CL, Alloing G, Tan MW, et al. A reverse genetic analysis of components of the Toll signaling pathway in Caenorhabditis elegans. Curr Biol 2001;11:809–821.
Ishii A, Matsuo A, Sawa H, Tsujita T, Shida K, Matsumoto M, et al. Lamprey TLRs with properties distinct from those of the variable lymphocyte receptors. J Immunol 2007;178:397–406.
Azumi K, De Santis R, De Tomaso A, Rigoutsos I, Yoshizaki F, Pinto MR, et al. Genomic analysis of immunity in a Urochordate and the emergence of the vertebrate immune system: “waiting for Godot”. Immunogenetics 2003;55:570–581.
Hibino T, Loza-Coll M, Messier C, Majeske AJ, Cohen AH, Terwilliger DP, et al. The immune gene repertoire encoded in the purple sea urchin genome. Dev Biol 2006;300:349–365.
Inamori K, Koori K, Mishima C, Muta T, Kawabata S. A horseshoe crab receptor structurally related to Drosophila Toll. J Endotoxin Res 2000;6:397–399.
Yang LS, Yin ZX, Liao JX, Huang XD, Guo CJ, Weng SP, et al. A Toll receptor in shrimp. Mol Immunol 2007;44:1999–2008.
Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 1999;11:443–451.
Takeuchi O, Kawai T, Muhlradt PF, Morr M, Radolf JD, Zychlinsky A, et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol 2001;13:933–940.
Takeuchi O, Sato S, Horiuchi T, Hoshino K, Takeda K, Dong Z, et al. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol 2002;169:10–14.
Jin MS, Kim SE, Heo JY, Lee ME, Kim HM, Paik SG, et al. Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 2007;130:1071–1082.
Netea MG, Van Der Graaf CA, Vonk AG, Verschueren I, Van Der Meer JW, Kullberg BJ. The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J Infect Dis 2002;185:1483–1489.
Brown GD, Herre J, Williams DL, Willment JA, Marshall AS, Gordon S. Dectin-1 mediates the biological effects of beta-glucans. J Exp Med 2003;197:1119–1124.
Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 1999;162:3749–3752.
Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998;282:2085–2088.
Nagai Y, Akashi S, Nagafuku M, Ogata M, Iwakura Y, Akira S, et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol 2002;3:667–672.
Jiang Z, Georgel P, Du X, Shamel L, Sovath S, Mudd S, et al. CD14 is required for MyD88-independent LPS signaling. Nat Immunol 2005;6:565–570.
Jack RS, Fan X, Bernheiden M, Rune G, Ehlers M, Weber A, et al. Lipopolysaccharide-binding protein is required to combat a murine gram-negative bacterial infection. Nature 1997;389:742–745.
Kim HM, Park BS, Kim JI, Kim SE, Lee J, Oh SC, et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell 2007;130:906–917.
Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001;410:1099–1103.
Uematsu S, Jang MH, Chevrier N, Guo Z, Kumagai Y, Yamamoto M, et al. Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells. Nat Immunol 2006;7:868–874.
Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, et al. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 2005;308:1626–1629.
Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, et al. A toll-like receptor that prevents infection by uropathogenic bacteria. Science 2004;303:1522–1526.
Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001;413:732–738.
Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 2002;3:196–200.
Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, et al. A Toll-like receptor recognizes bacterial DNA. Nature 2000;408:740–745.
Barton GM, Kagan JC, Medzhitov R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat Immunol 2006;7:49–56.
Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004;303:1529–1531.
Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004;303:1526–1529.
Ishii KJ, Akira S. Innate immune recognition of, and regulation by, DNA. Trends Immunol 2006;27:525–532.
Coban C, Ishii KJ, Kawai T, Hemmi H, Sato S, Uematsu S, et al. Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J Exp Med 2005;201:19–25.
Coban C, Ishii KJ, Uematsu S, Arisue N, Sato S, Yamamoto M, et al. Pathological role of Toll-like receptor signaling in cerebral malaria. Int Immunol 2007;19:67–79.
Medzhitov R, Preston-Hurlburt P, Kopp E, Stadlen A, Chen C, Ghosh S, et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 1998;2:253–258.
Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003;301:640–643.
Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 2002;420:324–329.
Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 2003;4:1144–1150.
Hemmi H, Kaisho T, Takeda K, Akira S. The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J Immunol 2003;170:3059–3064.
Takeuchi O, Takeda K, Hoshino K, Adachi O, Ogawa T, Akira S. Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades. Int Immunol 2000;12:113–117.
Suzuki N, Suzuki S, Duncan GS, Millar DG, Wada T, Mirtsos C, et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 2002;416:750–756.
Swantek JL, Tsen MF, Cobb MH, Thomas JA. IL-1 receptor-associated kinase modulates host responsiveness to endotoxin. J Immunol 2000;164:4301–4306.
Yamamoto M, Okamoto T, Takeda K, Sato S, Sanjo H, Uematsu S, et al. Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling. Nat Immunol 2006;7:962–970.
Sato S, Sanjo H, Takeda K, Ninomiya-Tsuji J, Yamamoto M, Kawai T, et al. Essential function for the kinase TAK1 in innate and adaptive immune responses. Nat Immunol 2005;6:1087–1095.
Shim JH, Xiao C, Paschal AE, Bailey ST, Rao P, Hayden MS, et al. TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev 2005;19:2668–2681.
Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 2005;434:243–249.
Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, et al. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat Immunol 2004;5:503–507.
McWhirter SM, Fitzgerald KA, Rosains J, Rowe DC, Golenbock DT, Maniatis T. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc Natl Acad Sci U S A 2004;101:233–238.
Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J. Triggering the interferon antiviral response through an IKK-related pathway. Science 2003;300:1148–1151.
Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, et al. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 2003;4:491–496.
Cao W, Liu YJ. Innate immune functions of plasmacytoid dendritic cells. Curr Opin Immunol 2007;19:24–30.
Hoshino K, Sugiyama T, Matsumoto M, Tanaka T, Saito M, Hemmi H, et al. IkappaB kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9. Nature 2006;440:949–953.
Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, Yamamoto M, et al. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 2004;5:1061–1068.
Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, et al. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7-and TLR9-mediated interferon-{alpha} induction. J Exp Med 2005;201:915–923.
Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 2007;315:1398–1401.
Kanneganti TD, Lamkanfi M, Nunez G. Intracellular NOD-like receptors in host defense and disease. Immunity 2007;27:549–559.
DeYoung BJ, Innes RW. Plant NBS-LRR proteins in pathogen sensing and host defense. Nat Immunol 2006;7:1243–1249.
Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 2003;4:702–707.
Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jehanno M, Viala J, et al. Nod1 detects a unique muropeptide from gramnegative bacterial peptidoglycan. Science 2003;300:1584–1587.
Chin AI, Dempsey PW, Bruhn K, Miller JF, Xu Y, Cheng G. Involvement of receptor-interacting protein 2 in innate and adaptive immune responses. Nature 2002;416:190–194.
Kobayashi K, Inohara N, Hernandez LD, Galan JE, Nunez G, Janeway CA, et al. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 2002;416:194–199.
Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 2004;20:319–325.
Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002;10:417–426.
Kanneganti TD, Ozoren N, Body-Malapel M, Amer A, Park JH, Franchi L, et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 2006;440:233–236.
Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 2006;440:228–232.
Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237–241.
Mariathasan S, Weiss DS, Dixit VM, Monack DM. Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis. J Exp Med 2005;202:1043–1049.
Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 2004;430:213–218.
Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozoren N, Jagirdar R, et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat Immunol 2006;7:576–582.
Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol 2006;7:569–575.
Wright EK, Goodart SA, Growney JD, Hadinoto V, Endrizzi MG, Long EM, et al. Naip5 affects host susceptibility to the intracellular pathogen Legionella pneumophila. Curr Biol 2003;13:27–36.
Diez E, Lee SH, Gauthier S, Yaraghi Z, Tremblay M, Vidal S, et al. Bircle is the gene within the Lgn1 locus associated with resistance to Legionella pneumophila. Nat Genet 2003;33:55–60.
Lamkanfi M, Amer A, Kanneganti TD, Munoz-Planillo R, Chen G, Vandenabeele P, et al. The Nod-like receptor family member Naip5/Birc1e restricts Legionella pneumophila growth independently of caspase-1 activation. J Immunol 2007;178:8022–8027.
Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, Vance RE, et al. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol 2006;7:318–325.
Yoneyama M, Fujita T. Function of RIG-I-like receptors in antiviral innate immunity. J Biol Chem 2007;282:15315–15318.
Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 2006;441:101–105.
Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, Kato H, et al. 5′-Triphosphate RNA is the ligand for RIG-I. Science 2006;314:994–997.
Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P, Weber F, et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 2006;314:997–1001.
Venkataraman T, Valdes M, Elsby R, Kakuta S, Caceres G, Saijo S, et al. Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses. J Immunol 2007;178:6444–6455.
Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, et al. IPS-1, an adaptor triggering RIG-I-and Mda5-mediated type I interferon induction. Nat Immunol 2005;6:981–988.
Seth RB, Sun L, Ea CK, Chen ZJ. Identification and characterization of MAVS a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 2005;122:669–682.
Gack MU, Shin YC, Joo CH, Urano T, Liang C, Sun L, et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 2007;446:916–920.
Arimoto K, Takahashi H, Hishiki T, Konishi H, Fujita T, Shimotohno K. Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proc Natl Acad Sci U S A 2007;104:7500–7505.
Jounai N, Takeshita F, Kobiyama K, Sawano A, Miyawaki A, Xin KQ, et al. The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc Natl Acad Sci U S A 2007;104:14050–14055.
Ishii KJ, Coban C, Kato H, Takahashi K, Torii Y, Takeshita F, et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat Immunol 2006;7:40–48.
Stetson DB, Medzhitov R. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 2006;24:93–103.
Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H, Ban T, et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 2007;448:501–505.
Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity 2005;23:19–28.
Kumar H, Kawai T, Kato H, Sato S, Takahashi K, Coban C, et al. Essential role of IPS-1 in innate immune responses against RNA viruses. J Exp Med 2006;203:1795–1803.
Sun Q, Sun L, Liu HH, Chen X, Seth RB, Forman J, et al. The specific and essential role of MAVS in antiviral innate immune responses. Immunity 2006;24:633–642.
Jung A, Kato H, Kumagai Y, Kumar H, Kawai T, Takeuchi O, et al. Lymphocytoid choriomeningitis virus activates plasmacytoid dendritic cells and induces a cytotoxic T-cell response via MyD88. J Virol 2008;82:196–206.
Koyama S, Ishii KJ, Kumar H, Tanimoto T, Coban C, Uematsu S, et al. Differential role of TLR-and RLR-signaling in the immune responses to influenza A virus infection and vaccination. J Immunol 2007;179:4711–4720.
Kumagai Y, Takeuchi O, Kato H, Kumar H, Matsui K, Morii E, et al. Alveolar macrophages are the primary interferon-alpha producer in pulmonary infection with RNA viruses. Immunity 2007;27:240–252.
Krug A, French AR, Barchet W, Fischer JA, Dzionek A, Pingel JT, et al. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 2004;21:107–119.
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 2003;198:513–520.
Lund JM, Linehan MM, Iijima N, Iwasaki A. Cutting Edge: Plasmacytoid dendritic cells provide innate immune protection against mucosal viral infection in situ. J Immunol 2006;177:7510–7514.
ClustalW WWW System. http://clustalw.ddbj.nig.ac.jp Accessed 21 Mar 2008.
Comput Appl Biosci. 1996 Aug;12(4):357–8. Tree View: an application to display phylogenetic trees on personal computers. Page RD. Division of Environmental and Evolutionary Biology University of Glasgow UK. r.page@bio.gla.ac.uk
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Kumagai, Y., Takeuchi, O. & Akira, S. Pathogen recognition by innate receptors. J Infect Chemother 14, 86–92 (2008). https://doi.org/10.1007/s10156-008-0596-1
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DOI: https://doi.org/10.1007/s10156-008-0596-1