The Journal of Experimental Medicine
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Published 4 August 2003. doi:10.1084/jem.20030162
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© Rockefeller University Press, 0022-1007/2003/8/513 $5.00
The Journal of Experimental Medicine, Volume 198, Number 3, 513-520

Brief Definitive Report

 Toll-like Receptor 9–mediated Recognition of Herpes Simplex Virus-2 by Plasmacytoid Dendritic Cells

Jennifer Lund1, Ayuko Sato2, Shizuo Akira3, Ruslan Medzhitov1 and Akiko Iwasaki1,2

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-1intB220+ pDCs from mouse bone marrow secreted high levels of IFN-{alpha} in response to either live or UV-inactivated Herpes simplex virus-2 (HSV-2). Next, we identified that IFN-{alpha} 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-{alpha} 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-{alpha} secretion from pDCs and that inhibitory CpG oligonucleotide treatment diminished HSV-induced IFN-{alpha} 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-{alpha} 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-{alpha} by pDCs.

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


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