When Two Strands Are Better Than One: The Mediators and Modulators of the Cellular Responses to Double-Stranded RNA

Jacobs, Bertram L.; Langland, Jeffrey

doi:10.1006/viro.1996.0259

Cited by 543 publications

(411 citation statements)

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“…[18][19][20] It has been reported that replication and transcription of the viral genome of single-stranded viral RNA viruses and many DNA viruses often lead to the formation of cytosolic dsRNA. 45,46 Thus, dsRNA could induce PKR activation. Recently, 2AP was suggested to have suppressive effect on other kinases; 47 therefore, further studies to explore the roles of PKR and other kinases in VZV infection are needed.…”

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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“…Activation of PKR and of the transcription factor NF-κB are important mediators of dsRNA signal transduction in other cell types [13,49,50], and these pathways have been shown to transduce at least part of the effects of dsRNA, including apoptosis, in beta cells [21,22,45,50]. We observed both an induction of the NF-κB precursor p105 and of several well defined beta-cell NF-κB-dependent genes, such as iNOS [51], MCP-1 [41] and MnSOD [52]; there was also a nearly 10-fold increase in PKR mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

“…During viral infection, accumulation of the viral replicative intermediate double stranded RNA (dsRNA) in the cytosol of the infected cell stimulates antiviral activities, such as dsRNA-dependent protein kinase (PKR) activation, type I interferons and NO production and a general inhibition of protein translation [13,14]. These antiviral responses can be mimicked by treatment of cells with the synthetic dsRNA polyinosinic-polycytidylic acid (PIC) [15,16].…”

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confidence: 99%

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

et al. 2003

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Aims/hypothesis. Viral infections and local production of IFN-γ might contribute to beta-cell dysfunction/ death in Type 1 Diabetes. Double stranded RNA (dsRNA) accumulates in the cytosol of viral-infected cells, and exposure of purified rat beta cells to dsRNA (tested in the form of polyinosinic-polycytidylic acid, PIC) in combination with IFN-γ results in beta-cell dysfunction and apoptosis. To elucidate the molecular mechanisms involved in PIC + IFN-γ-effects, we determined the global profile of genes modified by these agents in primary rat beta cells. Methods. FACS-purified rat beta cells were cultured for 6 or 24 h in control condition or with IFN-γ, PIC or a combination of both agents. The gene expression profile was analysed in duplicate by high-density oligonucleotide arrays representing 5000 full-length genes and 3000 EST's. Changes of greater than or equal to 2.5-fold were considered as relevant.Results. Following a 6-or 24-h treatment with IFN-γ, PIC or IFN-γ and PIC, we observed changes in the expression of 51 to 189 genes. IFN-γ modified the expression of MHC-related genes, and also of genes involved in beta-cell metabolism, protein processing, cytokines and signal transduction. PIC affected preferentially the expression of genes related to cell adhesion, cytokines and dsRNA signal transduction, transcription factors and MHC. PIC and/or IFN-γ up-regulated the expression of several chemokines and cytokines that could contribute to mononuclear cell homing and activation during viral infection, while IFN-γ induced a positive feedback on its own signal transduction. PIC + IFN-γ inhibited insulin and GLUT-2 expression without modifying pdx-1 mRNA expression. Conclusion/interpretation. This study provides the first comprehensive characterization of the molecular responses of primary beta cells to dsRNA + IFN-γ, two agents that are probably present in the beta cell milieu during the course of virally-induced insulitis and Type 1 Diabetes. Based on these findings, we propose an integrated model for the molecular mechanisms involved in dsRNA + IFN-γ induced beta-cell dysfunction and death. [Diabetologia (2003[Diabetologia ( ) 46:1641[Diabetologia ( -1657

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“…Virus infection is often accompanied by generation of dsRNA or long base‐paired RNAs (Jacobs & Langland, 1996; Weber et al , 2006; Son et al , 2015). These can serve as substrates for Dicer to generate virus‐derived siRNAs (viRNAs) (Ding & Voinnet, 2007; Kemp & Imler, 2009; Swarts et al , 2014; tenOever, 2016) that are loaded onto RISC and target complementary viral RNA to block virus replication.…”

Section: Introductionmentioning

confidence: 99%

Inactivation of the type I interferon pathway reveals long double‐stranded RNA‐mediated RNA interference in mammalian cells

et al. 2016

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RNA interference (RNAi) elicited by long double‐stranded (ds) or base‐paired viral RNA constitutes the major mechanism of antiviral defence in plants and invertebrates. In contrast, it is controversial whether it acts in chordates. Rather, in vertebrates, viral RNAs induce a distinct defence system known as the interferon (IFN) response. Here, we tested the possibility that the IFN response masks or inhibits antiviral RNAi in mammalian cells. Consistent with that notion, we find that sequence‐specific gene silencing can be triggered by long dsRNAs in differentiated mouse cells rendered deficient in components of the IFN pathway. This unveiled response is dependent on the canonical RNAi machinery and is lost upon treatment of IFN‐responsive cells with type I IFN. Notably, transfection with long dsRNA specifically vaccinates IFN‐deficient cells against infection with viruses bearing a homologous sequence. Thus, our data reveal that RNAi constitutes an ancient antiviral strategy conserved from plants to mammals that precedes but has not been superseded by vertebrate evolution of the IFN system.

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When Two Strands Are Better Than One: The Mediators and Modulators of the Cellular Responses to Double-Stranded RNA

Cited by 543 publications

References 0 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

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

Inactivation of the type I interferon pathway reveals long double‐stranded RNA‐mediated RNA interference in mammalian cells

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