Toll-like receptor 9–mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells

J Lund, A Sato, S Akira, R Medzhitov… - The Journal of …, 2003 - rupress.org
The Journal of experimental medicine, 2003rupress.org
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-α in
response to either live or UV-inactivated Herpes simplex virus-2 (HSV-2). Next, we identified
that IFN-α secretion by pDCs required the expression of the adaptor molecule MyD88 …
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-α in response to either live or UV-inactivated Herpes simplex virus-2 (HSV-2). Next, we identified that IFN-α 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-α 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-α secretion from pDCs and that inhibitory CpG oligonucleotide treatment diminished HSV-induced IFN-α 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-α 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-α by pDCs.
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