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Journal of Virology, October 2006, p. 9943-9950, Vol. 80, No. 20
0022-538X/06/$08.00+0     doi:10.1128/JVI.01036-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Induction of Innate Immunity against Herpes Simplex Virus Type 2 Infection via Local Delivery of Toll-Like Receptor Ligands Correlates with Beta Interferon Production

Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada

Received 19 May 2006/ Accepted 4 August 2006

Toll-like receptors (TLRs) constitute a family of innate receptors that recognize and respond to a wide spectrum of microorganisms, including fungi, bacteria, viruses, and protozoa. Previous studies have demonstrated that ligands for TLR3 and TLR9 induce potent innate antiviral responses against herpes simplex virus type 2 (HSV-2). However, the factor(s) involved in this innate protection is not well-defined. Here we report that production of beta interferon (IFN-ß) but not production of IFN-, IFN-, or tumor necrosis factor alpha (TNF-) strongly correlates with innate protection against HSV-2. Local delivery of poly(I:C) and CpG oligodeoxynucleotides induced significant production of IFN-ß in the genital tract and provided complete protection against intravaginal (IVAG) HSV-2 challenge. There was no detectable IFN-ß in mice treated with ligands for TLR4 or TLR2, and these mice were not protected against subsequent IVAG HSV-2 challenge. There was no correlation between levels of TNF- or IFN- in the genital tract and protection against IVAG HSV-2 challenge following TLR ligand delivery. Both TNF-^–/– and IFN-^–/– mice were protected against IVAG HSV-2 challenge following local delivery of poly(I:C). To confirm that type I interferon, particularly IFN-ß, mediates innate protection, mice unresponsive to type I interferons (IFN-/ßR^–/– mice) and mice lacking IFN regulatory factor-3 (IRF-3^–/– mice) were treated with poly(I:C) and then challenged with IVAG HSV-2. There was no protection against HSV-2 infection following poly(I:C) treatment of IFN-/ßR^–/– or IRF-3^–/– mice. Local delivery of murine recombinant IFN-ß protected C57BL/6 and IRF-3^–/– mice against IVAG HSV-2 challenge. Results from these in vivo studies clearly suggest a strong correlation between IFN-ß production and innate antiviral immunity against HSV-2.

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