Herpes simplex virus type-1 induces IFN-alpha production via Toll-like receptor 9-dependent and -independent pathways.
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-alpha, and whether the production of IFN-alpha 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-alpha in response to oligodeoxynucleotides containing CpG motifs, but in response to HSV-1 the majority of IFN-alpha was produced by other cell types. Moreover, IFN-alpha 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-alpha in the absence of functional TLR9, whereas spleen pDC did not. Heat treatment of HSV-1 abolished maturation and IFN-alpha production from all TLR9-deficient DC but not WT DC. Thus pDC and non-pDC produce IFN-alpha in response to HSV-1 via both TLR9-independent and -dependent pathways.
Hochrein
Hubertus
H
Institute of Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, 81675 Munich, Germany. h.hochrein@lrz.tum.de
Schlatter
Beatrix
B
O'Keeffe
Meredith
M
Wagner
Cornelia
C
Schmitz
Frank
F
Schiemann
Matthias
M
Bauer
Stefan
S
Suter
Mark
M
Wagner
Hermann
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D006561:Herpes Simplex / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006358:Hot Temperature; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000378:metabolism / Q000821:virology; D051217:Toll-Like Receptor 9
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma