A Protective Role of Locally Administered Immunostimulatory CpG Oligodeoxynucleotide in a Mouse Model of Genital Herpes Infection

Harandi, Ali M.; Eriksson, Kristina; Holmgren, Jan

doi:10.1128/jvi.77.2.953-962.2003

Cited by 143 publications

(128 citation statements)

References 56 publications

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“…A HSV-2 infection in vivo normally leads to a robust cytokine response with induction of type I IFNs, IL-6, IL-12, RANTES, and TNF-␣ among others (17,(33)(34)(35). The data presented in Figs.…”

Section: Tlr2 and Tlr9 Cooperatively Induce Cytokine Production Durinmentioning

confidence: 94%

“…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%

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

Sørensen

Reinert

Malmgaard

et al. 2008

The Journal of Immunology

158

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: Tlr2 and Tlr9 Cooperatively Induce Cytokine Production Durinmentioning

confidence: 94%

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

158

165

View full text Add to dashboard Cite

show abstract

“…Indeed, CpG DNA induces stronger immune responses with less toxicity than other adjuvants (Lonsdorf et al, 2003;Oumouna et al, 2005;Weeratna et al, 2000). CpG ODNs bind to TLR9 and preferentially induce Th1-biased immune responses with the production of cytokines such as IL-12 and IFN-c (Harandi et al, 2003;Rao et al, 2004). In this study, we used ODN 1826, a mouse-specific CpG ODN, to mature proteinpulsed DCs.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cells pulsed with hepatitis C virus NS3 protein induce immune responses and protection from infection with recombinant vaccinia virus expressing NS3

Huang

Xiang

et al. 2006

Journal of General Virology

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Infections with Hepatitis C virus (HCV) pose a serious health problem worldwide. In this study, the hypothesis that adoptive transfer of dendritic cells (DCs) pulsed with HCV NS3 protein and matured with an oligodeoxynucleotide (ODN) containing CpG motifs (CpG) ex vivo would initiate potent HCV-specific protective immune responses in vivo was tested. NS3 protein was efficiently transduced into DCs and treatment of DCs with CpG ODN induced phenotypic maturation and specifically increased the expression of CD40. DCs matured with CpG ODN produced higher interleukin 12 levels and a stronger allogeneic T-cell response compared with untreated DCs. Notably, there were no differences between NS3-pulsed DCs and DCs pulsed with a control protein with respect to phenotype, cytokine production or mixed lymphocyte reaction, indicating that transduction with NS3 protein did not impair DC functions. Compared with the untreated NS3-pulsed DCs, the NS3-pulsed DCs matured with CpG ODN induced stronger cellular immune responses including enhanced cytotoxicity, higher interferon-c production and stronger lymphocyte proliferation. Upon challenge with a recombinant vaccinia virus expressing NS3, all mice immunized with NS3-pulsed DCs showed a significant reduction in vaccinia virus titres when compared with mock-immunized mice. However, the NS3-pulsed DCs matured with CpG ODN induced higher levels of protection compared with the untreated NS3-pulsed DCs. These data are the first to show that NS3-pulsed DCs induce specific immune responses and provide protection from viral challenge, and also demonstrate that CpG ODNs, which have a proven safety profile, would be useful in the development of DC vaccines. INTRODUCTIONInfections with Hepatitis C virus (HCV) pose a serious health problem worldwide. An estimated 170 million people are currently infected, which amounts to 3 % of the world population. About 80 % of infected people remain chronic carriers and are at high risk of developing severe liver disease including cirrhosis and hepatocellular carcinoma (WHO, 1999). Treatment with interferon-a (IFN-a) and ribavirin is the only effective therapy against HCV infection, but the overall response rate is only 40-50 % (Fried et al., 2002;Manns et al., 2001). Currently, there is no licensed vaccine against HCV; therefore, developing strategies for vaccination as well as for treatment of HCV infection is of great importance.Dendritic cells (DCs) are the most potent type of antigen presenting cells (APCs) and are responsible for the initiation and maintenance of immune responses. Situated in peripheral tissues and in lymphoid organs, DCs are uniquely suited to detect and capture pathogens. They express members of the recently identified Toll-like receptor (TLR) family, which bind common chemical moieties associated with microbial organisms. TLR ligands include bacterial lipopolysaccharide, lipopeptides, hypomethylated CpG DNA motifs, dsRNA and flagellin (Akira et al., 2001;Iwasaki & Medzhitov, 2004). TLR signalling triggers a maturation program...

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“…There are conflicting observations regarding the roles of T cells and IFN-γ. A previous study has shown that the protection requires IFN-γ, IL-12, IL-18, and T cells (6) while others have demonstrated that complete protection is conferred by CpG ODN in the absence of any lymphocytes (RAG2 -/-γc -/-) (9) or IFN-γ (5). However, the precise cellular and molecular mechanism by which CpG ODN provides protection against HSV-2 challenge is unclear, which may hinder the clinical application of CpG ODN as a microbicide.…”

Section: Introductionmentioning

confidence: 99%

A crucial role for plasmacytoid dendritic cells in antiviral protection by CpG ODN-based vaginal microbicide

Shen

Iwasaki

2006

Journal of Clinical Investigation

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Topical microbicides represent a promising new approach to preventing HIV and other sexually transmitted infections. TLR agonists are ideal candidates for microbicides, as they trigger a multitude of antiviral genes effective against a broad range of viruses. Although vaginal application of CpG oligodeoxynucleotides (ODNs) and poly I:C has been shown to protect mice from genital herpes infection, the mechanism by which these agents provide protection remains unclear. Here, we show that plasmacytoid DCs (pDCs) are required for CpG ODNmediated protection against lethal vaginal challenge with herpes simplex virus type 2 (HSV-2). Moreover, we demonstrate that cells of both the hematopoietic and stromal compartments must respond to CpG ODN via TLR9 and to type I IFNs through IFN-αβ receptor (IFN-αβR) for protection. Thus, crosstalk between pDCs and vaginal stromal cells provides for optimal microbicide efficacy. Our results imply that temporally and spatially controlled targeting of CpG ODN to pDCs and epithelial cells can potentially maximize their effectiveness as microbicides while minimizing the associated inflammatory responses.

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A Protective Role of Locally Administered Immunostimulatory CpG Oligodeoxynucleotide in a Mouse Model of Genital Herpes Infection

Cited by 143 publications

References 56 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

Dendritic cells pulsed with hepatitis C virus NS3 protein induce immune responses and protection from infection with recombinant vaccinia virus expressing NS3

A crucial role for plasmacytoid dendritic cells in antiviral protection by CpG ODN-based vaginal microbicide

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