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Science 303 (5663): 1529-1531

Copyright © 2004 by the American Association for the Advancement of Science

Innate Antiviral Responses by Means of TLR7-Mediated Recognition of Single-Stranded RNA

Sandra S. Diebold,1 Tsuneyasu Kaisho,2,3 Hiroaki Hemmi,2 Shizuo Akira,2,4 Caetano Reis e Sousa1*

Abstract: Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-{alpha} in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.

1 Immunobiology Laboratory, Cancer Research UK, London Research Institute, London WC2A 3PX, UK.
2 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Yamadaoka 3-1, Suita City, Osaka 565–0871, Japan.
3 RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumiku, Yokohama City, Kanagawa 230–0045, Japan.
4 Akira Innate Immunity Project, ERATO, Japan Science and Technology Corporation, Osaka 565–0871, Japan.

* To whom correspondence should be addressed. E-mail: caetano{at}cancer.org.uk


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Innate Immune Responses in Human Monocyte-Derived Dendritic Cells Are Highly Dependent on the Size and the 5' Phosphorylation of RNA Molecules.
M. Jiang, P. Osterlund, L. P. Sarin, M. M. Poranen, D. H. Bamford, D. Guo, and I. Julkunen (2011)
J. Immunol. 187, 1713-1721
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Requirement of UNC93B1 Reveals a Critical Role for TLR7 in Host Resistance to Primary Infection with Trypanosoma cruzi.
B. C. Caetano, B. B. Carmo, M. B. Melo, A. Cerny, S. L. dos Santos, D. C. Bartholomeu, D. T. Golenbock, and R. T. Gazzinelli (2011)
J. Immunol. 187, 1903-1911
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Priming of Protective Anti-Listeria monocytogenes Memory CD8+ T Cells Requires a Functional SecA2 Secretion System.
M. Rahmoun, M. Gros, L. Campisi, D. Bassand, A. Lazzari, C. Massiera, E. Narni-Mancinelli, P. Gounon, and G. Lauvau (2011)
Infect. Immun. 79, 2396-2403
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Distinctive TLR7 Signaling, Type I IFN Production, and Attenuated Innate and Adaptive Immune Responses to Yellow Fever Virus in a Primate Reservoir Host.
J. N. Mandl, R. Akondy, B. Lawson, N. Kozyr, S. I. Staprans, R. Ahmed, and M. B. Feinberg (2011)
J. Immunol. 186, 6406-6416
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Small molecule Toll-like receptor 7 agonists localize to the MHC class II loading compartment of human plasmacytoid dendritic cells.
C. Russo, I. Cornella-Taracido, L. Galli-Stampino, R. Jain, E. Harrington, Y. Isome, S. Tavarini, C. Sammicheli, S. Nuti, M. L. Mbow, et al. (2011)
Blood 117, 5683-5691
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Plasmacytoid Dendritic Cells Promote Host Defense against Acute Pneumovirus Infection via the TLR7-MyD88-Dependent Signaling Pathway.
S. Davidson, G. Kaiko, Z. Loh, A. Lalwani, V. Zhang, K. Spann, S. Y. Foo, N. Hansbro, S. Uematsu, S. Akira, et al. (2011)
J. Immunol. 186, 5938-5948
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Bovine Plasmacytoid Dendritic Cells Are the Major Source of Type I Interferon in Response to Foot-and-Mouth Disease Virus In Vitro and In Vivo.
E. Reid, N. Juleff, S. Gubbins, H. Prentice, J. Seago, and B. Charleston (2011)
J. Virol. 85, 4297-4308
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Oligonucleotide Motifs That Disappear during the Evolution of Influenza Virus in Humans Increase Alpha Interferon Secretion by Plasmacytoid Dendritic Cells.
S. Jimenez-Baranda, B. Greenbaum, O. Manches, J. Handler, R. Rabadan, A. Levine, and N. Bhardwaj (2011)
J. Virol. 85, 3893-3904
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Antigen-Specific T-Cell Responses to a Recombinant Fowlpox Virus Are Dependent on MyD88 and Interleukin-18 and Independent of Toll-Like Receptor 7 (TLR7)- and TLR9-Mediated Innate Immune Recognition.
E. L. Lousberg, K. R. Diener, C. K. Fraser, S. Phipps, P. S. Foster, W. Chen, S. Uematsu, S. Akira, S. A. Robertson, M. P. Brown, et al. (2011)
J. Virol. 85, 3385-3396
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A Point Mutation in the Amino Terminus of TLR7 Abolishes Signaling without Affecting Ligand Binding.
C. Iavarone, K. Ramsauer, A. V. Kubarenko, J. C. Debasitis, I. Leykin, A. N. R. Weber, O. M. Siggs, B. Beutler, P. Zhang, G. Otten, et al. (2011)
J. Immunol. 186, 4213-4222
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Phagosomal signaling by Borrelia burgdorferi in human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-{beta}.
J. L. Cervantes, S. M. Dunham-Ems, C. J. La Vake, M. M. Petzke, B. Sahay, T. J. Sellati, J. D. Radolf, and J. C. Salazar (2011)
PNAS 108, 3683-3688
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Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria.
B. S. Franklin, S. T. Ishizaka, M. Lamphier, F. Gusovsky, H. Hansen, J. Rose, W. Zheng, M. A. Ataide, R. B. de Oliveira, D. T. Golenbock, et al. (2011)
PNAS 108, 3689-3694
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The Dual Functions of IL-1 Receptor-Associated Kinase 2 in TLR9-Mediated IFN and Proinflammatory Cytokine Production.
Y. Wan, T. W. Kim, M. Yu, H. Zhou, M. Yamashita, Z. Kang, W. Yin, J.-a. Wang, J. Thomas, G. C. Sen, et al. (2011)
J. Immunol. 186, 3006-3014
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