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

McMaster University, Hamilton, Ontario, Canada
Journal of Virology (Impact Factor: 4.44). 11/2006; 80(20):9943-50. DOI: 10.1128/JVI.01036-06
Source: PubMed


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-beta) but not production of IFN-alpha, IFN-gamma, or tumor necrosis factor alpha (TNF-alpha) strongly correlates with innate protection against HSV-2. Local delivery of poly(I:C) and CpG oligodeoxynucleotides induced significant production of IFN-beta in the genital tract and provided complete protection against intravaginal (IVAG) HSV-2 challenge. There was no detectable IFN-beta 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-alpha or IFN-gamma in the genital tract and protection against IVAG HSV-2 challenge following TLR ligand delivery. Both TNF-alpha(-/-) and IFN-gamma(-/-) mice were protected against IVAG HSV-2 challenge following local delivery of poly(I:C). To confirm that type I interferon, particularly IFN-beta, mediates innate protection, mice unresponsive to type I interferons (IFN-alpha/betaR(-/-) 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-alpha/betaR(-/-) or IRF-3(-/-) mice. Local delivery of murine recombinant IFN-beta 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-beta production and innate antiviral immunity against HSV-2.

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    • "The importance of TLR-9 in conferring protection against HSV-2 infections has also been demonstrated by Harandi and colleagues (93) who showed that administration of CpG-ODN is effective against HSV-2 challenge. Treatment limits viral replication and increases survival following HSV challenge (94). CpG does not directly inhibit the virus but acts to stimulate immune responses (95). "
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    • "Agonists of TLRs 3, 7, 8 and 9 have shown benefits in preventing initial infection and recurrences in several animal models of genital herpes (Ashkar et al., 2003, 2004; Bernstein et al., 2001; Gill et al., 2006; Herbst-Kralovetz and Pyles, 2006; McCluskie et al., 2006; Pyles et al., 2002). Our group also demonstrated that pre-treatment of mice with polyinosinic:polycytidylic acid (PIC), a TLR3 agonist, before intranasal inoculation of HSV-1 decreased HSE severity and mortality probably through an early production of IFN-b (Boivin et al., 2008). "
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