User Ratings

Easy to Follow Achieved Expected Results Overall Rating Add your comments

Toll‐Like Receptors

Kiyoshi Takeda¹, Shizuo Akira²

¹Osaka University, Osaka, Japan
²Osaka University and ERATO Japan Science and Technology Agency, Osaka, Japan

Publication Name:

Current Protocols in Immunology

Unit Number:

Unit 14.12

DOI:

10.1002/0471142735.im1412s77

Online Posting Date:

May, 2007

GO TO THE FULL TEXT:

PDF or HTML at Wiley Online Library

Are you the author of this protocol? Login or register and return to this page.

Abstract

This has led to the identification of several important roles for Toll receptors in mammals. This unit discusses mammalian Toll receptors (TLR1-10) that have an essential role in the innate immune recognition of microorganisms. Also discussed are TLR-mediated signaling pathways and antibodies that are available to detect specific TLRs.

Keywords: innate immunity; Toll-like receptors; NOD; RNA helicase; TIR domain

GO TO THE FULL PROTOCOL:

PDF or HTML at Wiley Online Library

Unit Introduction
Toll-Like Receptors in Mammals
TLR Signaling Pathways
TLR-Independent Recognition of Microorganisms
Literature Cited
Figures
Tables

GO TO THE FULL PROTOCOL:

PDF or HTML at Wiley Online Library

Figures

Figure 14.12.1

Signaling pathways via TLRs. TLR signaling pathways consist of two major cascades depending on TIR domain–containing adaptors, such as MyD88 and TRIF. MyD88 mediates activation of NF-B and subsequent induction of inflammatory cytokine genes via all TLRs except for TLR3. TRIF mediates TLR3- and TLR4-dependent activation of IRF3 and NF-B, and subsequent induction of IFN-. In pDCs, MyD88 also is responsible for TLR7- and TLR9-dependent activation of IRF7 leading to induction of IFN-/.

View Image
Figure 14.12.2

NOD-LRR proteins and microbial recognition. NOD1 and NOD2 recognize iE-DAP and MDP, respectively, and activate NF-B via RIP2. NAIP5 and IPAF recognize flagellin derived from L. pneumophila and S. typhimurium, whereas Nalp3 recognizes bacterial NA, ATP, and uric-acid crystals. NAIP5, IPAF, and Nalp3 induce cleavage of pro-IL-1 through ASC-dependent caspase-1 activation.

View Image
Figure 14.12.3

RNA helicases and viral recognition. During viral replication dsRNA is produced, which is recognized by RIG-I and MDA5. IPS-1, which is localized on the mitochondrial membrane, interacts with RIG-I/MDA5, and mediates activation of NF-B and IRF3/IRF7. FADD and RIP1 are involved in NF-B activation via IPS-1, whereas TBK1 and IKKi mediate IRF activation.

View Image

Literature Cited

Literature Cited
	Akira, S. and Takeda, K. 2004. Toll-like receptor signalling. Nat. Rev. Immunol. 4:499-511.
	Akira, S., Uematsu, S., and Takeuchi, O. 2006. Pathogen recognition and innate immunity. Cell 124:783-801.
	Alexopoulou, L., Holt, A.C., Medzhitov, R., and Flavell, R.A. 2001. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732-738.
	Alexopoulou, L., Thomas, V., Schnare, M., Lobet, Y., Anguita, J., Schoen, R.T., Medzhitov, R., Fikrig, E., and Flavell, R.A. 2002. Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat. Med. 8:878-884.
	Asea, A., Rehli, M., Kabingu, E., Boch, J.A., Bare, O., Auron, P.E., Stevenson, M.A., and Calderwood, S.K. 2002. Novel signal transduction pathway utilized by extracellular HSP70: Role of toll-like receptor (TLR) 2 and TLR4. J. Biol. Chem. 277:15028-15034.
	Barrat, F.J., Meeker, T., Gregorio, J., Chan, J.H., Uematsu, S., Akira, S., Chang, B., Duramad, O., and Coffman, R.L. 2005. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J. Exp. Med. 202:1131-1139.
	Berland, R., Fernandez, L., Kari, E., Han, J.H., Lomakin, I., Akira, S., Wortis, H.H., Kearney, J.F., Ucci, A.A., and Imanishi-Kari, T. 2006. Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Immunity 25:429-440.
	Boule, M.W., Broughton, C., Mackay, F., Akira, S., Marshak-Rothstein, A., and Rifkin, I.R. 2004. Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes. J. Exp. Med. 199:1631-1640.
	Byrd-Leifer, C.A., Block, E.F., Takeda, K., Akira, S., and Ding, A. 2001. The role of MyD88 and TLR4 in the LPS-mimetic activity of Taxol. Eur. J. Immunol. 31:2448-2457.
	Chamaillard, M., Hashimoto, M., Horie, Y., Masumoto, J., Qiu, S., Saab, L., Ogura, Y., Kawasaki, A., Fukase, K., Kusumoto, S., Valvano, M.A., Foster, S.J., Mak, T.W., Nunez, G., and Inohara, N. 2003. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat. Immunol. 4:702-707.
	Christensen, S.R., Shupe, J., Nickerson, K., Kashgarian, M., Flavell, R.A., and Shlomchik, M.J. 2006. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25:417-428.
	da Silva Correia, J., Soldau, K., Christen, U., Tobias, P.S., and Ulevitch, R.J. 2001. Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. Transfer from CD14 to TLR4 and MD-2. J. Biol. Chem. 276:21129-21135.
	Diebold, S.S., Kaiso, T., Hemmi, H., Akira, S., and Reise e Sousa, C. 2004. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529-1531.
	Diez, E., Lee, S.H., Gauthier, S., Yaraghi, Z., Tremblay, M., Vidal, S., and Gros, P. 2003. Birc1e is the gene within the Lgn1 locus associated with resistance to Legionella pneumophila. Nat. Genet. 33:55-60.
	Divanovic, S., Trompette, A., Atabani, S.F., Madan, R., Golenbock, D.T., Visintin, A., Finberg, R.W., Tarakhovsky, A., Vogel, S.N., Belkaid, Y., Kurt-Jones, E.A., and Karp, C.L. 2005. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nat. Immunol. 6:571-578.
	Edelmann, K.H., Richardson-Burns, S., Alexopoulou, L., Tyler, K.L., Flavell, R.A., and Oldstone, M.B. 2004. Does Toll-like receptor 3 play a biological role in virus infections Virology 322:231-238.
	Fitzgerald, K.A., Rowe, D.C., Barnes, B.J., Caffrey, D.R., Visintin, A., Latz, E., Monks, B., Pitha, P.M., and Golenbock, D.T. 2003. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J. Exp. Med. 198:1043-1055.
	Franchi, L., Amer, A., Body-Malapel, M., Kanneganti, T.D., Ozoren, N., Jagirdar, R., Inohara, N., Vandenabeele, P., Bertin, J., Coyle, A., Grant, E.P., and Nunez, G. 2006. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in Salmonella-infected macrophages. Nat. Immunol. 7:576-582.
	Gewirtz, A.T., Navas, T.A., Lyons, S., Godowski, P.J., and Madara, J.L. 2001. Cutting edge: Bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J. Immunol. 167:1882-1885.
	Girardin, S.E., Boneca, I.G., Carneiro, L.A., Antignac, A., Jehanno, M., Viala, J., Tedin, K., Taha, M.K., Labigne, A., Zahringer, U., Coyle, A.J., DiStefano, P.S., Bertin, J., Sansonetti, P.J., and Philpott, D.J. 2003. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science 300:1584-1587.
	Gorden, K.K., Qiu, X.X., Binsfeld, C.C., Vasilakos, J.P., and Alkan, S.S. 2006. Cutting edge: Activation of murine TLR8 by a combination of imidazoquinoline immune response modifiers and PolyT oligodeoxynucleotides. J. Immunol. 177:6584-6587.
	Hacker, H., Redecke, V., Blagoev, B., Kratchmarova, I., Hsu, L.C., Wang, G.G., Kamps, M.P., Raz, E., Wagner, H., Hacker, G., Mann, M., and Karin, M. 2006. Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439:204-207.
	Hawn, T.R., Verbon, A., Lettinga, K.D., Zhao, L.P., Li, S.S., Laws, R.J., Skerrett, S.J., Beutler, B., Schroeder, L., Nachman, A., Ozinsky, A., Smith, K.D., and Aderem, A. 2003. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease. J. Exp. Med. 198:1563-1572.
	Hayashi, F., Smith, K.D., Ozinsky, A., Hawn, T.R., Yi, E.C., Goodlett, D.R., Eng, J.K., Akira, S., Underhill, D.M., and Aderem, A. 2001. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410:1099-1103.
	Heil, F., Hemmi, H., Hochrein, H., Ampenberger, F., Kirschning, C., Akira, S., Lipford, G., Wagner, H., and Bauer, S. 2004. Species-specific recognition of single-stranded RNA via Toll-like receptors 7 and 8. Science 303:1526-1529.
	Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., and Akira, S. 2000. A Toll-like receptor recognizes bacterial DNA. Nature 408:740-745.
	Hemmi, H., Kaisho, T., Takeuchi, O., Sato, S., Sanjo, H., Hoshino, K., Horiuchi, T., Tomizawa, H., Takeda, K., and Akira, S. 2002. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3:196-200.
	Hemmi, H., Takeuchi, O., Sato, S., Yamamoto, M., Kaisho, T., Sanjo, H., Kawai, T., Hoshino, K., Takeda, K., and Akira, S. 2004. The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J. Exp. Med. 199:1641-1650.
	Hoebe, K., Du, X., Georgel, P., Janssen, E., Tabeta, K., Kim, S.O., Goode, J., Lin, P., Mann, N., Mudd, S., Crozat, K., Sovath, S., Han, J., and Beutler, B. 2003. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424:743-748.
	Honda, K., Yanai, H., Mizutani, T., Negishi, H., Shimada, N., Suzuki, N., Ohba, Y., Takaoka, A., Yeh, W.C., and Taniguchi, T. 2004. Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc. Natl. Acad. Sci. U.S.A. 101:15416-15421.
	Honda, K., Ohba, Y., Yanai, H., Negishi, H., Mizutani, T., Takaoka, A., Taya, C., and Taniguchi, T. 2005. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434:1035-1040.
	Honda, K., Takaoka, A., and Taniguchi, T. 2006. Type I interferon [correction of inteferon] gene induction by the interferon regulatory factor family of transcription factors. Immunity 25:349-360.
	Horng, T., Barton, G.M., Flavell, R.A., and Medzhitov, R. 2002. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420:329-333.
	Hornung, V., Ellegast, J., Kim, S., Brzozka, K., Jung, A., Kato, H., Poeck, H., Akira, S., Conzelmann, K.K., Schlee, M., Endres, S., and Hartmann, G. 2006. 5¢-Triphosphate RNA is the ligand for RIG-I. Science 314:994-997.
	Hoshino, K., Takeuchi, O., Kawai, T., Sanjo, H., Ogawa, T., Takeda, Y., Takeda, K., and Akira, S. 1999. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: Evidence for TLR4 as the Lps gene product. J. Immunol. 162:3749-3752.
	Hoshino, K., Sugiyama, T., Matsumoto, M., Tanaka, T., Saito, M., Hemmi, H., Ohara, O., Akira, S., and Kaisho, T. 2006. IkappaB kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9. Nature 440:949-953.
	Imler, J.L. and Hoffmann, J.A. 2001. Toll receptors in innate immunity. Trends Cell Biol. 11:304-311.
	Inohara, N. and Nunez, G. 2003. NODs: Intracellular proteins involved in inflammation and apoptosis. Nat. Rev. Immunol. 3:371-382.
	Inohara, N., Chamaillard, M. McDonald, C., and Nunez, G. 2005. NOD-LRR proteins: Role in host-microbial interactions and inflammatory disease. Annu. Rev. Biochem. 74:355-383.
	Jiang, Q., Akashi, S., Miyake, K., and Petty, H.R. 2000. Lipopolysaccharide induces physical proximity between CD14 and toll-like receptor 4 (TLR4) prior to nuclear translocation of NF-kappa B. J. Immunol. 165:3541-3544.
	Kanneganti, T.D., Ozoren, N., Body-Malapel, M., Amer, A., Park, J.H., Franchi, L., Whitfield, J., Barchet, W., Colonna, M., Vandenabeele, P., Bertin, J., Coyle, A., Grant, E.P., Akira, S., and Nunez, G. 2006. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440:233-236.
	Kato, H., Sato, S., Yoneyama, M., Yamamoto, M., Uematsu, S., Matsui, K., Tsujimura, T., Takeda, K., Fujita, T., Takeuchi, O., and Akira, S. 2005. Cell type-specific involvement of RIG-I in antiviral response. Immunity 23:19-28.
	Kato, H., Takeuchi, O., Sato, S., Yoneyama, M., Yamamoto, M., Matsui, K., Uematsu, S., Jung, A., Kawai, T., Ishii, K.J., Yamaguchi, O., Otsu, K., Tsujimura, T., Koh, C.S., Reis e Sousa, C., Matsuura, Y., Fujita, T., and Akira, S. 2006. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101-105.
	Kawai, T., Adachi, O., Ogawa, T., Takeda, K., and Akira, S. 1999. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11:115-122.
	Kawai, T., Sato, S., Ishii, K.J., Coban, C., Hemmi, H., Yamamoto, M., Terai, K., Matsuda, M., Inoue, J., Uematsu, S., Takeuchi, O., and Akira, S. 2004. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol. 5:1061-1068.
	Kawai, T., Takahashi, K., Sato, S., Coban, C., Kumar, H., Kato, H., Ishii, K.J., Takeuchi, O., and Akira, S. 2005. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6:981-988.
	Kawasaki, K., Akashi, S., Shimazu, R., Yoshida, T., Miyake, K., and Nishijima, M. 2000. Mouse toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J. Biol. Chem. 275:2251-2254.
	Krug, A., Rothenfusser, S., Hornung, V., Jahrsdorfer, B., Blackwell, S., Ballas, Z.K., Endres, S., Krieg, A.M., and Hartmann, G. 2001. Identification of CpG oligonucleotide sequences with high induction of IFN-alpha/beta in plasmacytoid dendritic cells. Eur. J. Immunol. 31:2154-2163.
	Kurt-Jones, E.A., Popova, L., Kwinn, L., Haynes, L.M., Jones, L.P., Tripp, R.A., Walsh, E.E., Freeman, M.W., Golenbock, D.T., Anderson, L.J., and Finberg, R.W. 2000. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat. Immunol. 1:398-401.
	Lau, C.M., Broughton, C., Tabor, A.S., Akira, S., Flavell, R.A., Mamula, M.J., Christensen, S.R., Shlomchik, M.J., Viglianti, G.A., Rifkin, I.R., and Marshak-Rothstein, A. 2005. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202:1171-1177.
	Leadbetter, E.A., Rifkin, I.R., Hohlbaum, A.M., Beaudette, B.C., Shlomchik, M.J., and Marshak-Rothstein, A. 2002. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603-607.
	Lund, J.M., Alexopoulou, L., Sato, A., Karow, M., Adams, N.C., Gale, N.W., Iwasaki, A., and Flavell, R.A. 2004. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl. Acad. Sci. U.S.A. 101:5598-5603.
	Mariathasan, S., Newton, K., Monack, D.M., Vucic, D., French, D.M., Lee, W.P., Roose-Girma, M., Erickson, S., and Dixit, V.M. 2004. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430:213-218.
	Mariathasan, S., Weiss, D.S., Newton, K., McBride, J., O'Rourke, K., Roose-Girma, M., Lee, W.P., Weinrauch, Y., Monack, D.M., and Dixit, V.M. 2006. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228-232.
	Marshak-Rothstein, A. 2006. Toll-like receptors in systemic autoimmune disease. Nat. Rev. Immunol. 6:823-835.
	Martinon, F., Burns, K., and Tschopp, J. 2002. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 10:417-426.
	Martinon, F., Petrilli, V., Mayor, A., Tardivel, A., and Tschopp, J. 2006. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237-241.
	McWhirter, S.M., Fitzgerald, K.A., Rosains, J., Rowe, D.C., Golenbock, D.T., and Maniatis, T. 2004. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc. Natl. Acad. Sci. U.S.A. 101:233-238.
	Medzhitov, R., Preston-Hurlburt, P., and Janeway, C.A. Jr. 1997. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394-397.
	Meylan, E., Burns, K., Hofmann, K., Blancheteau, V., Martinon, F., Kelliher, M., and Tschopp, J. 2004. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat. Immunol. 5:503-507.
	Meylan, E., Curran, J., Hofmann, K., Moradpour, D., Binder, M., Bartenschlager, R., and Tschopp, J. 2005. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167-1172.
	Miao, E.A., Alpuche-Aranda, C.M., Dors, M., Clark, A.E., Bader, M.W., Miller, S.I., and Aderem, A. 2006. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat. Immunol. 7:569-575.
	Molofsky, A.B., Byrne, B.G., Whitfield, N.N., Madigan, C.A., Fuse, E.T., Tateda, K., and Swanson, M.S. 2006. Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. J. Exp. Med. 203:1093-1104.
	Nagai, Y., Akashi, S., Nagafuku, M., Ogata, M., Iwakura, Y., Akira, S., Kitamura, T., Kosugi, A., Kimoto, M., and Miyake, K. 2002. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat. Immunol. 3:667-672.
	Oganesyan, G., Saha, S.K., Guo, B., He, J.Q., Shahangian, A., Zarnegar, B., Perry, A., and Cheng, G. 2006. Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 439:208-211.
	Ohashi, K., Burkart, V., Flohe, S., and Kolb, H. 2000. Cutting edge: Heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J. Immunol. 164:558-561.
	Okamura, Y., Watari, M., Jerud, E.S., Young, D.W., Ishizaka, S.T., Rose, J., Chow, J.C., and Strauss, J.F. 3rd. 2001. The extra domain A of fibronectin activates Toll-like receptor 4. J. Biol. Chem. 276:10229-10233.
	Ozinsky, A., Underhill, D.M., Fontenot, J.D., Hajjar, A.M., Smith, K.D., Wilson, C.B., Schroeder, L., and Aderem, A. 2000. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors. Proc. Natl. Acad. Sci. U.S.A. 97:13766-13771.
	Peng, G., Guo, Z., Kiniwa, Y., Voo, K.S., Peng, W., Fu, T., Wang, D.Y., Li, Y., Wang, H.Y., and Wang, R.F. 2005. Toll-like receptor 8-mediated reversal of CD4⁺ regulatory T cell function. Science 309:1380-1384.
	Perry, A.K., Chow, E.K., Goodnough, J.B., Yeh, W.C., and Cheng, G. 2004. Differential requirement for TANK-binding kinase-1 in type I interferon responses to toll-like receptor activation and viral infection. J. Exp. Med. 199:1651-1658.
	Pichlmair, A., Schulz, O., Tan, C.P., Naslund, T.I., Liljestrom, P., Weber, F., and Reis e Sousa, C. 2006. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5¢-phosphates. Science 314:997-1001.
	Pisitkun, P., Deane, J.A., Difilippantonio, M.J., Tarasenko, T., Satterthwaite, A.B., and Bolland, S. 2006. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312:1669-1672.
	Poltorak, A., He, X., Smirnova, I., Liu, M.Y., Van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., Freudenberg, M., Ricciardi-Castagnoli, P., Layton, B., and Beutler, B. 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene. Science 282:2085-2088.
	Rassa, J.C., Meyers, J.L., Zhang, Y., Kudaravalli, R., and Ross, S.R. 2002. Murine retroviruses activate B cells via interaction with Toll-like receptor 4. Proc. Natl. Acad. Sci. U.S.A. 99:2281-2286.
	Schulz, O., Diebold, S.S., Chen, M., Naslund, T.I., Nolte, M.A., Alexopoulou, L., Azuma, Y.T., Flavell, R.A., Liljestrom, P., and Reis e Sousa, C. 2005. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433:887-892.
	Seth, R.B., Sun, L., Ea, C.K., and Chen, Z.J. 2005. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122:669-682.
	Sharma, S., tenOever, B.R., Grandvaux, N., Zhou, G.P., Lin, R., and Hiscott, J. 2003. Triggering the interferon antiviral response through an IKK-related pathway. Science 300:1148-1151.
	Smith, K.D., Andersen-Nissen, E., Hayashi, F., Strobe, K., Bergman, M.A., Barrett, S.L., Cookson, B.T., and Aderem, A. 2003. Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat. Immunol. 4:1247-1253.
	Takeuchi, O., Kawai, T., Muhlradt, P.F., Morr, M., Radolf, J.D., Zychlinsky, A., Takeda, K., and Akira, S. 2001. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 13:933-940.
	Takeuchi, O., Sato, S., Horiuchi, T., Hoshino, K., Takeda, K., Dong, Z., Modlin, R.L., and Akira, S. 2002. Cutting edge: Role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169:10-14.
	Termeer, C., Benedix, F., Sleeman, J., Fieber, C., Voith, U., Ahrens, T., Miyake, K., Freudenberg, M., Galanos, C., and Simon, J.C. 2002. Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J. Exp. Med. 195:99-111.
	Uematsu, S., Sato, S., Yamamoto, M., Hirotani, T., Kato, H., Takeshita, F., Matsuda, M., Coban, C., Ishii, K.J., Kawai, T., Takeuchi, O., and Akira, S. 2005. 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. 201:915-923.
	Uematsu, S., Jang, M.H., Chevrier, N., Guo, Z., Kumagai, Y., Yamamoto, M., Kato, H., Sougawa, N., Matsui, H., Kuwata, H., Hemmi, H., Coban, C., Kawai, T., Ishii, K.J., Takeuchi, O., Miyasaka, M., Takeda, K., and Akira, S. 2006. Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells. Nat. Immunol. 7:868-874.
	Vabulas, R.M., Ahmad-Nejad, P., da Costa, C., Miethke, T., Kirschning, C.J., Hacker, H., and Wagner, H. 2001. Endocytosed HSP60s use Toll-like receptor 2 (TLR2) and TLR4 to activate the Toll/interleukin-1 receptor signaling pathway in innate immune cells. J. Biol. Chem. 276:31332-31339.
	Vabulas, R.M., Ahmad-Nejad, P., Ghose, S., Kirschning, C.J., Issels, R.D., and Wagner, H. 2002. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J. Biol. Chem. 277:15107-15112.
	Vollmer, J., Tluk, S., Schmitz, C., Hamm, S., Jurk, M., Forsbach, A., Akira, S., Kelly, K.M., Reeves, W.H., Bauer, S., and Krieg, A.M. 2005. Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8. J. Exp. Med. 202:1575-1585.
	Wang, T., Town, T., Alexopoulou, L., Anderson, J.F., Fikrig, E., and Flavell, R.A. 2004. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat. Med. 10:1366-1373.
	Wyllie, D.H., Kiss-Toth, E., Visintin, A., Smith, S.C., Boussouf, S., Segal, D.M., Duff, G.W., and Dower, S.K. 2000. Evidence for an accessory protein function for Toll-like receptor 1 in anti-bacterial responses. J. Immunol. 165:7125-7132.
	Xu, L.G., Wang, Y.Y., Han, K.J., Li, L.Y., Zhai, Z., and Shu, H.B. 2005. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol. Cell 19:727-740.
	Yamamoto, M., Sato, S., Hemmi, H., Sanjo, H., Uematsu, S., Kaisho, T., Hoshino, K., Takeuchi, O., Kobayashi, M., Fujita, T., Takeda, K., and Akira, S. 2002. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420:324-329.
	Yamamoto, M., Sato, S., Hemmi, H., Hoshino, K., Kaisho, T., Sanjo, H., Takeuchi, O., Sugiyama, M., Okabe, M., Takeda, K., and Akira, S. 2003a. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301:640-643.
	Yamamoto, M., Sato, S., Hemmi, H., Uematsu, S., Hoshino, K., Kaisho, T., Takeuchi, O., Takeda, K., and Akira, S. 2003b. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat. Immunol. 4:1144-1150.
	Yarovinsky, F., Zhang, D., Andersen, J.F., Bannenberg, G.L., Serhan, C.N., Hayden, M.S., Hieny, S., Sutterwala, F.S., Flavell, R.A., Ghosh, S., and Sher, A. 2005. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308:1626-1629.
	Yoneyama, M., Kikuchi, M., Natsukawa, T., Shinobu, N., Imaizumi, T., Miyagishi, M., Taira, K., Akira, S., and Fujita, T. 2004. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5:730-737.
	Zamboni, D.S., Kobayashi, K.S., Kohlsdorf, T., Ogura, Y., Long, E.M., Vance, R.E., Kuida, K., Mariathasan, S., Dixit, V.M., Flavell, R.A., Dietrich, W.F., and Roy, C.R. 2006. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat. Immunol. 7:318-325.
	Zhang, D., Zhang, G., Hayden, M.S., Greenblatt, M.B., Bussey, C., Flavell, R.A., and Ghosh, S. 2004. A Toll-like receptor that prevents infection by uropathogenic bacteria. Science 303:1522-1526.