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Brief Definitive Report

¹ Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
² Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520
³ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, SORST of Japan Science and Technology Corporation, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan

Address correspondence to A. Iwasaki, Department of Epidemiology and Public Health, 60 College St., LEPH 716, New Haven, CT 06510. Phone: 203-785-2919; Fax: 203-785-7552; email: akiko.iwasaki{at}yale.edu

Plasmacytoid dendritic cells (pDCs) have been identified as a potent secretor of the type I interferons (IFNs) in response to CpG as well as several viruses. In this study, we examined the molecular mechanism of virus recognition by pDCs. First, we demonstrated that the CD11c⁺Gr-1^intB220⁺ pDCs from mouse bone marrow secreted high levels of IFN- in response to either live or UV-inactivated Herpes simplex virus-2 (HSV-2). Next, we identified that IFN- secretion by pDCs required the expression of the adaptor molecule MyD88, suggesting the involvement of a Toll-like receptor (TLR) in HSV-2 recognition. To test whether a TLR mediates HSV-2–induced IFN- secretion from pDCs, various knockout mice were examined. These experiments revealed a clear requirement for TLR9 in this process. Further, we demonstrated that purified HSV-2 DNA can trigger IFN- secretion from pDCs and that inhibitory CpG oligonucleotide treatment diminished HSV-induced IFN- secretion by pDCs in a dose-dependent manner. The recognition of HSV-2 by TLR9 was mediated through an endocytic pathway that was inhibited by chloroquine or bafilomycin A1. The strict requirement for TLR9 in IFN- secretion was further confirmed by the inoculation of HSV-2 in vivo. Therefore, these results demonstrate a novel mechanism whereby the genomic DNA of a virus can engage TLR9 and result in the secretion of IFN- by pDCs.

Key Words: type I interferons • CpG motif • innate immunity • virus infection • DNA virus

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• Hayashi, K., Hooper, L. C., Chin, M. S., Nagineni, C. N., Detrick, B., Hooks, J. J. (2006). Herpes simplex virus 1 (HSV-1) DNA and immune complex (HSV-1-human IgG) elicit vigorous interleukin 6 release from infected corneal cells via Toll-like receptors.. J. Gen. Virol. 87: 2161-2169 [Abstract] [Full Text]  
• Feldmann, G., Nischalke, H. D., Nattermann, J., Banas, B., Berg, T., Teschendorf, C., Schmiegel, W., Duhrsen, U., Halangk, J., Iwan, A., Sauerbruch, T., Caselmann, W. H., Spengler, U. (2006). Induction of Interleukin-6 by Hepatitis C Virus Core Protein in Hepatitis C-Associated Mixed Cryoglobulinemia and B-Cell Non-Hodgkin's Lymphoma. Clin. Cancer Res. 12: 4491-4498 [Abstract] [Full Text]  
• Hidmark, A. S., Nordstrom, E. K. L., Dosenovic, P., Forsell, M. N. E., Liljestrom, P., Karlsson Hedestam, G. B. (2006). Humoral Responses against Coimmunized Protein Antigen but Not against Alphavirus-Encoded Antigens Require Alpha/Beta Interferon Signaling. J. Virol. 80: 7100-7110 [Abstract] [Full Text]  
• Montoya, C. J., Jie, H.-B., Al-Harthi, L., Mulder, C., Patino, P. J., Rugeles, M. T., Krieg, A. M., Landay, A. L., Wilson, S. B. (2006). Activation of Plasmacytoid Dendritic Cells with TLR9 Agonists Initiates Invariant NKT Cell-Mediated Cross-Talk with Myeloid Dendritic Cells. J. Immunol. 177: 1028-1039 [Abstract] [Full Text]  
• Bertoletti, A., Gehring, A. J. (2006). The immune response during hepatitis B virus infection. J. Gen. Virol. 87: 1439-1449 [Abstract] [Full Text]  
• Guloglu, F. B., Roman, C. A. J. (2006). Precursor B Cell Receptor Signaling Activity Can Be Uncoupled from Surface Expression.. J. Immunol. 176: 6862-6872 [Abstract] [Full Text]  
• Kuo, C.-C., Lin, W.-T., Liang, C.-M., Liang, S.-M. (2006). Class I and III Phosphatidylinositol 3'-Kinase Play Distinct Roles in TLR Signaling Pathway. J. Immunol. 176: 5943-5949 [Abstract] [Full Text]  
• Szomolanyi-Tsuda, E., Liang, X., Welsh, R. M., Kurt-Jones, E. A., Finberg, R. W. (2006). Role for TLR2 in NK Cell-Mediated Control of Murine Cytomegalovirus In Vivo. J. Virol. 80: 4286-4291 [Abstract] [Full Text]  
• Melchjorsen, J., Siren, J., Julkunen, I., Paludan, S. R., Matikainen, S. (2006). Induction of cytokine expression by herpes simplex virus in human monocyte-derived macrophages and dendritic cells is dependent on virus replication and is counteracted by ICP27 targeting NF-{kappa}B and IRF-3.. J. Gen. Virol. 87: 1099-1108 [Abstract] [Full Text]  
• Yrlid, U., Milling, S. W. F., Miller, J. L., Cartland, S., Jenkins, C. D., MacPherson, G. G. (2006). Regulation of Intestinal Dendritic Cell Migration and Activation by Plasmacytoid Dendritic Cells, TNF-{alpha} and Type 1 IFNs after Feeding a TLR7/8 Ligand. J. Immunol. 176: 5205-5212 [Abstract] [Full Text]  
• Andersen, J. M., Al-Khairy, D., Ingalls, R. R. (2006). Innate Immunity at the Mucosal Surface: Role of Toll-Like Receptor 3 and Toll-Like Receptor 9 in Cervical Epithelial Cell Responses to Microbial Pathogens. Biol. Reprod. 74: 824-831 [Abstract] [Full Text]  
• Lopez, C. B., Yount, J. S., Moran, T. M. (2006). Toll-like receptor-independent triggering of dendritic cell maturation by viruses.. J. Virol. 80: 3128-3134 [Full Text]  
• Matikainen, S., Siren, J., Tissari, J., Veckman, V., Pirhonen, J., Severa, M., Sun, Q., Lin, R., Meri, S., Uze, G., Hiscott, J., Julkunen, I. (2006). Tumor Necrosis Factor Alpha Enhances Influenza A Virus-Induced Expression of Antiviral Cytokines by Activating RIG-I Gene Expression.. J. Virol. 80: 3515-3522 [Abstract] [Full Text]  
• Yu, F.-S. X., Hazlett, L. D. (2006). Toll-like Receptors and the Eye.. IOVS 47: 1255-1263 [Full Text]  

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