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

Gill, Navkiran; Deacon, Philip M.; Lichty, Brian D.; Mossman, Karen; Ashkar, Ali A.

doi:10.1128/jvi.01036-06

Cited by 93 publications

(106 citation statements)

References 37 publications

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“…Additionally, the TLR2 Ϫ/Ϫ mice responded to the infection with an impaired inflammatory response (17,21,23). TLR9 has been examined in the vaginal infection model, with several studies showing a protective effect of locally administered TLR9 ligand CpG before HSV infection (33,(43)(44)(45)(46)(47). For TLR9 Ϫ/Ϫ mice one study found these mice to be more susceptible to HSV-2 (27), yet another found no differences (22).…”

Section: Discussionmentioning

confidence: 99%

TLR2 and TLR9 Synergistically Control Herpes Simplex Virus Infection in the Brain

Sørensen

Reinert

Malmgaard

et al. 2008

The Journal of Immunology

160

165

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Viruses are recognized by the innate immune system through pattern recognition receptors (PRRs). For instance, HSV virions and genomic DNA are recognized by TLR2 and TLR9, respectively. Although several viruses and viral components have been shown to stimulate cells through TLRs, only very few studies have defined essential roles for single TLRs in innate immune defense in vivo. This could suggest that PRRs act in concert to mount the first line of defense against virus infections. To test this hypothesis we have examined the host response of C57BL/6, TLR2−/−, TLR9−/−, and TLR2/9−/− mice toward HSV-2 infection. After a systemic infection, the cytokine serum response was markedly reduced in the double knockout mice, but only partly affected in either strain of the single knockout mice. This was supported by in vitro data showing that HSV-induced cytokine expression relayed on TLR2 and TLR9 in a cytokine- and cell type-dependent manner. With respect to the cellular response to infection, we found that recruitment but not activation of NK cells was impaired in TLR2/9−/− mice. Importantly, the viral load in the brain, but not liver, was significantly higher in the brain of TLR2/9−/− mice whereas the viral loads in organs of single knockout mice were statistically indistinguishable from C57BL/6 mice. In the brain we found that TNF-α and the IFN-stimulated gene CXCL9 were expressed during infection and were dependent on either TLR2 or TLR9. Thus, TLR2 and TLR9 synergistically stimulate innate antiviral activities, thereby protecting against HSV infection in the brain.

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Section: Discussionmentioning

confidence: 99%

TLR2 and TLR9 Synergistically Control Herpes Simplex Virus Infection in the Brain

Sørensen

Reinert

Malmgaard

et al. 2008

The Journal of Immunology

160

165

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“…Thus, poly(I:C) might have most potential as a topical strategy that could be applied immediately within 24 h after exposure to curb local spread. In addition, the ability of TLR3 ligation to limit herpes simplex virus infection (4,28,33,63,76) would also help to control the spread of HIV (11).…”

Section: Discussionmentioning

confidence: 99%

Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

Trapp

Derby

Singer

et al. 2009

J Virol

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“…Synthetic ligands for TLR3 and 9 (polyinosinic : polycytidylic acid (poly I : C) and CpG oligodeoxynucleotides respectively) were shown to be effective in treating viral infections like HIV, HBV, HCV, herpes virus or FV (McClary et al, 2000;Ashkar et al, 2004;Isogawa et al, 2005;Gill et al, 2006;Kraft et al, 2007;McHutchison et al, 2007;Trapp et al, 2009;Gibbert et al, 2010). We and others have shown in mice that the therapeutic effect of the TLR ligand used depends on the induction of type I IFN, as therapeutic treatment with the different TLR ligands is not effective in mice deficient in the type I IFN receptor (IFNAR -/-) (McClary et al, 2000;Isogawa et al, 2005;Gill et al, 2006;Gibbert et al, 2010). For the hepadnavirus woodchuck hepatitis virus (WHV), it was shown that the stimulation of peripheral blood lymphocytes from acute and chronic WHV-infected woodchucks with the TLR3 ligand poly I : C reduced viral titres in vitro and in vivo, and this was due to the expression of specific woodchuck IFN-a subtypes (Lu et al, 2008).…”

Section: Drugs That Induce Endogenous Ifn-a Productionmentioning

confidence: 99%

IFN‐α subtypes: distinct biological activities in anti‐viral therapy

Gibbert

Schlaak

Yang

et al. 2013

British J Pharmacology

154

138

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During most viral infections, the immediate host response is characterized by an induction of type I IFN. These cytokines have various biological activities, including anti‐viral, anti‐proliferative and immunomodulatory effects. After induction, they bind to their IFN‐α/β receptor, which leads to downstream signalling resulting in the expression of numerous different IFN‐stimulated genes. These genes encode anti‐viral proteins that directly inhibit viral replication as well as modulate immune function. Thus, the induction of type I IFN is a very powerful tool for the host to fight virus infections. Many viruses evade this response by various strategies like the direct suppression of IFN induction or inhibition of the IFN signalling pathway. Therefore, the therapeutic application of exogenous type I IFN or molecules that induce strong IFN responses should be of great potential for future immunotherapies against viral infections. Type I IFN is currently used as a treatment in chronic hepatitis B and C virus infection, but as yet is not widely utilized for other viral infections. One reason for this restricted clinical use is that type I IFN belongs to a multigene family that includes 13 different IFN‐α subtypes and IFN‐β, whose individual anti‐viral and immunomodulatory properties have so far not been investigated in detail to improve IFN therapy against viral infections in humans. In this review, we summarize the recent achievements in defining the distinct biological functions of type I IFN subtypes in cell culture and in animal models of viral infection as well as their clinical usage in chronic hepatitis virus infections.

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

Cited by 93 publications

References 37 publications

TLR2 and TLR9 Synergistically Control Herpes Simplex Virus Infection in the Brain

TLR2 and TLR9 Synergistically Control Herpes Simplex Virus Infection in the Brain

Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

IFN‐α subtypes: distinct biological activities in anti‐viral therapy

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