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 L8N 3Z5, 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.

Download full-text


Available from: Brian Lichty, Oct 10, 2015
11 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Immunotherapies that can either activate or suppress innate immune responses are being investigated as treatments against infectious diseases and the pathology they can cause. The objective of these therapies is to elicit protective immune responses thereby limiting the harm inflicted by the pathogen. The Toll-like receptor (TLR) signaling pathway plays critical roles in numerous host immune defenses and has been identified as an immunotherapeutic target against the consequences of infectious challenge. This review focuses on some of the recent advances being made in the development of TLR-ligands as potential prophylactic and/or therapeutic agents.
    Frontiers in Immunology 03/2014; 5:79. DOI:10.3389/fimmu.2014.00079
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: We evaluated the effects of agonists and antagonist of toll-like receptor (TLR) 9 in comparison with a TLR3 agonist in a mouse model of herpes simplex virus type 1 (HSV-1) encephalitis (HSE). BALB/c mice received a single intranasal dose of either a TLR3 agonist (polyinosinic:polycytidylic acid; PIC), TLR9 agonists (oligodeoxynucleotides (ODNs) 1585, 1826 or 2395) or a TLR9 antagonist (ODN 2088), 1day before and, for selected groups, 3days after infection with HSV-1. Mice that received the pre-treatment with vehicle, PIC, ODNs 1585, 1826, 2395 and 2088 before infection had survival rates of 25%, 65%, 55%, 40%, 55% and 30%, respectively (P<0.05 for PIC and ODNs 1585 and 2395 versus vehicle). Infected mice subsequently treated with vehicle, ODNs 2395 and 2088 had survival rates of 9%, 0% and 30%, respectively (P<0.05, ODN 2088 versus other groups). The pre-treatment of mice with ODN 2395 reduced both the viral load (P<0.05 at day 5) and the production of CCL2, IL-6 and CCL5 at days 3, 4 and 5 (P<0.05 for IL-6 at day 3 and P<0.05 for CCL2 and CCL5 at day 4). Treatment of infected mice with ODN 2088 reduced the production of the same cytokines (P=0.07 for CCL2 and P=0.09 for IL-6 at day 5). Pre-treatment of mice with TLR9 agonists before infection reduces brain viral load and cytokine levels resulting in increased HSE survival rates. On the other hand, TLR9 antagonists can be helpful to control the inflammatory response that could be detrimental after infection.
    Antiviral research 10/2012; 96:414-21. DOI:10.1016/j.antiviral.2012.09.022 · 3.94 Impact Factor
  • Source
    • "HSV is a double-stranded DNA (dsDNA) virus known to have a double-stranded RNA (dsRNA) intermediate usually recognized by TLR3. Upon TLR3 recognition of the dsRNA derived from HSV-1 replication, the NF-κB pathway is activated, leading to production of type-I IFNs (48), which are crucial for HSV clearance (49). A recent study showed that the synthetic TLR3 agonist has protective effects in lethal HSV-1 encephalitis (50). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute viral encephalitis caused by neurotrophic viruses, such as mosquito-borne flaviviruses, is an emerging and re-emerging disease that represents an immense global health problem. Considerable progression has been made in understanding the pathogenesis of acute viral encephalitis, but the immune-pathological processes occurring during the progression of encephalitis and the roles played by various molecules and cellular components of the innate and adaptive systems still remain undefined. Recent findings reveal the significant contribution of Toll-like receptors (TLRs) and regulatory CD4(+) T cells in the outcomes of infectious diseases caused by neurotrophic viruses. In this review, we discuss the ample evidence focused on the roles of TLRs and CD4(+) helper T cell subsets on the progression of acute viral encephalitis. Finally, we draw attention to the importance of these molecules and cellular components in defining the pathogenesis of acute viral encephalitis, thereby providing new therapeutic avenues for this disease.
    Immune Network 04/2012; 12(2):48-57. DOI:10.4110/in.2012.12.2.48
Show more