Herpes simplex virus type-1 induces IFN-α production via Toll-like receptor 9-dependent and -independent pathways

Hochrein, Hubertus; Schlatter, Beatrix; O’Keeffe, Meredith; Wagner, Cornelia; Schmitz, Frank; Schiemann, Matthias; Bauer, Stefan; Suter, Mark; Wagner, Hermann

doi:10.1073/pnas.0403555101

Cited by 393 publications

(356 citation statements)

References 32 publications

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“…This phenomenon has also been observed in herpes simplex virus infection in a murine system. 18,32 More evidence of TLR-independent recognition of RNA and DNA has been noted recently. dsRNA has been shown to be recognized by the cytoplasmic helicase domain of the helicase protein retinoic acid-induced gene 1.…”

Section: Discussionmentioning

confidence: 99%

IFN-α production by human mononuclear cells infected with varicella-zoster virus through TLR9-dependent and -independent pathways

Huang

Kuo

et al. 2011

Cell Mol Immunol

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Understanding the defense mechanisms of the host of an organism is important for infection control. In previous studies, we demonstrated that interferon-a (IFN-a), but not IL-12, was produced by human peripheral blood mononuclear cells infected with varicella-zoster virus (VZV). Here, we investigated what kind of cell(s) and which signal molecule(s) are involved in IFN-a production. Using cell isolation and ELISA, we found that plasmacytoid dendritic cells (pDCs) were responsible for IFN-a production during VZV infection. We also found that Toll-like receptor 9 (TLR9) was involved in VZV-induced IFN-a production because inhibitory CpG oligodeoxynucleotide inhibited IFN-a production. UV-inactivated VZV-induced IFN-a production was lower than that of active VZV, indicating another TLR9-independent pathway. Further studies demonstrated that double-stranded RNA-dependent protein kinase, but not DNA-dependent protein kinase was involved in VZV-induced IFN-a production. Together, these results suggest that pDCs play an important role in IFN-a production during VZV infection through TLR9-dependent and -independent pathways.

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Section: Discussionmentioning

confidence: 99%

IFN-α production by human mononuclear cells infected with varicella-zoster virus through TLR9-dependent and -independent pathways

Huang

Kuo

et al. 2011

Cell Mol Immunol

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“…3B, cytokine production against the Ad vector occurred mainly in conventional DC. It is noted that the TLR9-mediated innate immunity responses to DNA virus are cell type-specific and limited to plasmacytoid DC (50). The unidentified sensor receptor(s) for double-stranded Ad DNA or Ad capsid protein in conventional DC might play a critical role in the expression of inflammatory cytokines/chemokines and type I IFN.…”

Section: Discussionmentioning

confidence: 99%

Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production

Koizumi

Yamaguchi

Kono

et al. 2007

The Journal of Immunology

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Adenovirus (Ad) vectors are one of the most commonly used viral vectors in gene therapy clinical trials. However, they elicit a robust innate immune response and inflammatory responses. Improvement of the therapeutic index of Ad vector gene therapy requires elucidation of the mechanism of Ad vector-induced inflammation and cytokine/chemokine production as well as development of the safer vector. In the present study, we found that the fiber-modified Ad vector containing poly-lysine peptides in the fiber knob showed much lower serum IL-6 and aspartate aminotransferase levels (as a maker of liver toxicity) than the conventional Ad vector after i.v. administration, although the modified Ad vector showed higher transgene production in the liver than the conventional Ad vector. RT-PCR analysis showed that spleen, not liver, is the major site of cytokine, chemokine, and IFN expression. Splenic CD11c+ cells were found to secret cytokines. The tissue distribution of Ad vector DNA showed that spleen distribution was much reduced in this modified Ad vector, reflecting reduced IL-6 levels in serum. Liver toxicity by the conventional Ad vector was reduced by anti-IL-6R Ab, suggesting that IL-6 signaling is involved in liver toxicity and that decreased liver toxicity of the modified Ad vector was due in part to the reduced IL-6 production. This study contributes to an understanding of the biological mechanism in innate immune host responses and liver toxicity toward systemically administered Ad vectors and will help in designing safer gene therapy methods that can reduce robust innate immunity and inflammatory responses.

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“…TLR are pattern recognition receptors of the innate immune system for the detection of pathogen-derived microbial molecules [35]. The plasmacytoid DC (PDC) is specialised in the detection of viruses; it employs TLR9 to detect CpG motifs in viral DNA and produces large amounts of type I IFN (IFN-a and IFN-b), the signature cytokines of an anti-viral immune response [36][37][38][39]. CpG-activated PDC indirectly activate other immune cells such as monocytes [40,41], NK cells, c/d T cells [42] and memory a/b T cells [43,44].…”

Section: Introductionmentioning

confidence: 99%

CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cells

et al. 2005

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Human Va24 + Vb11 + natural killer T cells (NKT cells) are "natural memory" T cells that detect glycolipid antigens such as a-galactosylceramide (a-GalCer) presented on CD1d.In the present study we found that highly purified Va24 + NKT cells lack TLR9 mRNA, and thus are not sensitive towards stimulation with CpG oligodeoxynucleotides (ODN). Within PBMC, however, CpG ODN synergistically activated NKT cells stimulated with their cognate antigen a-GalCer. Depletion of plasmacytoid dendritic cells (PDC) or myeloid dendritic cells (MDC) revealed that both DC subsets were necessary for the synergistic activation of NKT cells by a-GalCer and CpG ODN. While PDC were responsible for the stimulation of NKT cells with CpG ODN, MDC but not PDC presented a-GalCer via CD1d. Partial activation of NKT cells was mediated by PDC-derived IFN-a, whereas full activation of NKT cells as indicated by IFN-c production required cell-tocell contact of PDC and NKT cells in addition to IFN-a; OX40 was involved in this interaction. We conclude that CpG-activated PDC enhance a-GalCer-specific NKT cell activation, and bias activated NKT cells towards a Th1 phenotype. Our results lead to a novel concept of PDC function: to regulate effector activity of antigen-stimulated T cells in a cell contact-dependent manner without the need of simultaneous presentation of the cognate T cell antigen. IntroductionNatural killer T (NKT) cells represent a small subset of non-conventional innate T cells with a restricted TCR repertoire for the recognition of glycolipid antigens presented on CD1d, an MHC class I-like molecule. NKT cells express markers of NK cells and exhibit an activated memory phenotype. Depending on the microenvironment and the type of stimulation, they can release large amounts of both Th1 and Th2 cytokines (especially IL-4 and IFN-c) and show cytotoxic activity in vitro (reviewed in [1][2][3]). In both mice and man NKT cells express a homologous semi-invariant TCR that in humans consists of a Va24 chain preferentially paired with a Vb11 chain [4]. In mice, NKT cells are most frequent in the liver (about 30% of hepatic T cells), bone marrow and thymus (reviewed in [5]). Smaller NKT cell populations are present in spleen and blood (reviewed in [5]). Similar to their murine counterparts, human NKT cells preferen-A. M., S. R. and V. H. equally contributed to this manuscript. tially accumulate in the liver though with a far lower frequency than in mice (4% of hepatic T cells) ([6, 7] and reviewed in [1,5]). Due to the conserved TCR, both mouse and human NKT cells recognise the same specific glycolipid antigen a-galactosylceramide (a-GalCer) when presented by CD1d molecules on antigen-presenting cells (APC) [8][9][10]. Originally isolated from a marine sponge, aGalCer was first described as an agent with strong antimetastatic activity in mice and later found to specifically activate NKT cells in a CD1d-restricted manner [8,11,12]. Glycolipid antigens similar to a-GalCer have been detected in certain bacteria and under some abnormal conditions...

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Herpes simplex virus type-1 induces IFN-α production via Toll-like receptor 9-dependent and -independent pathways

Cited by 393 publications

References 32 publications

IFN-α production by human mononuclear cells infected with varicella-zoster virus through TLR9-dependent and -independent pathways

IFN-α production by human mononuclear cells infected with varicella-zoster virus through TLR9-dependent and -independent pathways

Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production

CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cells

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