Recognition of single-stranded RNA viruses by Toll-like receptor 7.

Viral infection of mammalian host results in the activation of innate immune responses. Toll-like receptors (TLRs) have been shown to mediate the recognition of many types of pathogens, including viruses. The genomes of viruses possess unique characteristics that are not found in mammalian genomes, such as high CpG content and double-stranded RNA. These genomic nucleic acids serve as molecular signatures associated with viral infections. Here we show that TLR7 recognizes the single-stranded RNA viruses, vesicular stomatitis virus and influenza virus. The recognition of these viruses by plasmacytoid dendritic cells and B cells through TLR7 results in their activation of costimulatory molecules and production of cytokines. Moreover, this recognition required intact endocytic pathways. Mice deficient in either the TLR7 or the TLR adaptor protein MyD88 demonstrated reduced responses to in vivo infection with vesicular stomatitis virus. These results demonstrate microbial ligand recognition by TLR7 and provide insights into the pathways used by the innate immune cells in the recognition of viral pathogens.

[1]  Y. Fujiwara,et al.  Vascular endothelial cell lineage-specific promoter in transgenic mice. , 1995, Development.

[2]  A. F. Stewart,et al.  High-throughput engineering of the mouse genome coupled with high-resolution expression analysis , 2003, Nature Biotechnology.

[3]  J. Kahn,et al.  Recombinant vesicular stomatitis virus expressing respiratory syncytial virus (RSV) glycoproteins: RSV fusion protein can mediate infection and cell fusion. , 1999, Virology.

[4]  E. Walsh,et al.  Monoclonal antibodies to respiratory syncytial virus proteins: identification of the fusion protein , 1983, Journal of virology.

[5]  A. Helenius,et al.  Cell fusion by Semliki Forest, influenza, and vesicular stomatitis viruses , 1981, The Journal of cell biology.

[6]  S. Akira,et al.  Toll‐like receptor expression in murine DC subsets: lack of TLR7 expression by CD8α+ DC correlates with unresponsiveness to imidazoquinolines , 2003, European journal of immunology.

[7]  M. Gunn,et al.  Cd11c+B220+Gr-1+ Cells in Mouse Lymph Nodes and Spleen Display Characteristics of Plasmacytoid Dendritic Cells , 2001, The Journal of experimental medicine.

[8]  Jiahuai Han,et al.  Identification of Lps2 as a key transducer of MyD88-independent TIR signalling , 2003, Nature.

[9]  Persephone Borrow,et al.  Viral infection switches non-plasmacytoid dendritic cells into high interferon producers , 2003, Nature.

[10]  R. Medzhitov,et al.  Innate immune recognition: mechanisms and pathways , 2000, Immunological reviews.

[11]  G. Trinchieri,et al.  Flexibility of Mouse Classical and Plasmacytoid-derived Dendritic Cells in Directing T Helper Type 1 and 2 Cell Development , 2003, The Journal of experimental medicine.

[12]  S. Akira,et al.  Toll-like Receptor 9–mediated Recognition of Herpes Simplex Virus-2 by Plasmacytoid Dendritic Cells , 2003, The Journal of experimental medicine.

[13]  J. Reece,et al.  Heterogeneity of freshly isolated human tonsil dendritic cells demonstrated by intracellular markers, phagocytosis, and membrane dye transfer. , 2002, Cytometry.

[14]  M. Colonna,et al.  Virus-induced Interferon α Production by a Dendritic Cell Subset in the Absence of Feedback Signaling In Vivo , 2002, The Journal of experimental medicine.

[15]  Michael G. Katze,et al.  Viruses and interferon: a fight for supremacy , 2002, Nature Reviews Immunology.

[16]  S. Akira,et al.  Small anti-viral compounds activate immune cells via the TLR7 MyD88–dependent signaling pathway , 2002, Nature Immunology.

[17]  S. Akira,et al.  The Toll‐like receptor 7 (TLR7)‐specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily , 2003, European journal of immunology.

[18]  P. Feng,et al.  IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. , 1997, Science.

[19]  G. Trinchieri,et al.  Mouse Strain Differences in Plasmacytoid Dendritic Cell Frequency and Function Revealed by a Novel Monoclonal Antibody , 2003, The Journal of Immunology.

[20]  A. García-Sastre.  Mechanisms of inhibition of the host interferon α/β-mediated antiviral responses by viruses , 2002 .

[21]  S. Akira,et al.  Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway , 2003, Science.

[22]  Antonio Lanzavecchia,et al.  Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells , 2001, European journal of immunology.

[23]  M. Colonna,et al.  Interferon-producing cells: on the front line in immune responses against pathogens. , 2002, Current opinion in immunology.

[24]  J. Rose,et al.  Vesicular stomatitis virus glycoprotein containing the entire green fluorescent protein on its cytoplasmic domain is incorporated efficiently into virus particles. , 2001, Virology.

[25]  S. Akira,et al.  Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. , 2004, Blood.

[26]  G. Trinchieri,et al.  A leukocyte subset bearing HLA-DR antigens is responsible for in vitro alpha interferon production in response to viruses. , 1985, Natural immunity and cell growth regulation.

[27]  R. Flavell,et al.  Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 , 2001, Nature.

[28]  Marc Dalod,et al.  Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology , 2001, Nature Immunology.

[29]  Jongdae Lee,et al.  Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: Activation of Toll-like receptor 7 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. Doolittle,et al.  Homology between the glycoproteins of vesicular stomatitis virus and rabies virus , 1982, Journal of virology.

[31]  R. Vabulas,et al.  Bacterial CpG‐DNA and lipopolysaccharides activate Toll‐like receptors at distinct cellular compartments , 2002, European journal of immunology.

[32]  A. Helenius,et al.  Pathway of vesicular stomatitis virus entry leading to infection. , 1982, Journal of molecular biology.

[33]  S. Akira,et al.  Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. , 1998, Immunity.

[34]  S. Akira,et al.  Toll-like receptors and innate immunity. , 2006, Journal of molecular medicine.

[35]  S. Akira,et al.  A Toll-like receptor recognizes bacterial DNA , 2000, Nature.