Herpes simplex virus type-1 induces IFN-α production via Toll-like receptor 9-dependent and -independent pathways

Hubertus Hochrein, Beatrix Schlatter, Meredith O'Keeffe, Cornelia Wagner, Frank Schmitz, Matthias Schiemann, Stefan Bauer, Mark Suter, Hermann Wagner

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Type I IFN production in response to the DNA virus herpes simplex virus type-1 (HSV-1) is essential in controlling viral replication. We investigated whether plasmacytoid dendritic cells (pDC) were the major tissue source of IFN-α, and whether the production of IFN-α in response to HSV-1 depended on Toll-like receptor 9 (TLR9). Total spleen cells or bone marrow (BM) cells, or fractions thereof, including highly purified pDC, from WT, TLR9, and MyD88 knockout mice were stimulated with known ligands for TLR9 or active HSV-1. pDC freshly isolated from both spleen and BM were the major source of IFN-α in response to oligodeoxynucleotides containing CpG motifs, but in response to HSV-1 the majority of IFN-α was produced by other cell types. Moreover, IFN-α production by non-pDC was independent of TLR9. The tissue source determined whether pDC responded to HSV-1 in a strictly TLR9-dependent fashion. Freshly isolated BM pDC or pDC derived from culture of BM precursors with FMS-like tyrosine kinase-3 ligand, produced IFN-α in the absence of functional TLR9, whereas spleen pDC did not. Heat treatment of HSV-1 abolished maturation and IFN-α production from all TLR9-deficient DC but not WT DC. Thus pDC and non-pDC produce IFN-α in response to HSV-1 via both TLR9-independent and -dependent pathways.

Original languageEnglish
Pages (from-to)11416-11421
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number31
Publication statusPublished - 3 Aug 2004
Externally publishedYes

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