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Shou-wei Ding - One of the best experts on this subject based on the ideXlab platform.
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RNA-based antiViral Immunity
Nature Reviews Immunology, 2010Co-Authors: Shou-wei DingAbstract:In eukaryotic RNA-based antiViral Immunity, Viral double-stranded RNA is recognized as a pathogen-associated molecular pattern and processed into small interfering RNAs (siRNAs) by the host ribonuclease Dicer. After amplification by host RNA-dependent RNA polymerases in some cases, these virus-derived siRNAs guide specific antiViral Immunity through RNA interference and related RNA silencing effector mechanisms. Here, I review recent studies on the features of Viral siRNAs and other virus-derived small RNAs from virus-infected fungi, plants, insects, nematodes and vertebrates and discuss the innate and adaptive properties of RNA-based antiViral Immunity. RNA-based antiViral Immunity is active in diverse host species, which produce virus-derived small RNAs in infected cells and use them as specificity determinants to guide specific virus clearance. Specific members of the Dicer family of proteins, which encode RNA helicase, double-stranded RNA (dsRNA)-binding and dsRNA-specific RNase domains, function as pattern recognition receptors (PRRs) in fungi, plants and invertebrates to detect Viral dsRNA as a pathogen-associated molecular pattern (PAMP) and to further process it into virus-derived small interfering RNAs (siRNAs). Viral siRNAs are structurally similar to host endogenous siRNAs with monophosphate groups at the 5′ end and 2′- O -methyl groups at the 3′ end. They guide specific clearance of the invading Viral RNAs by members of the Argonaute (AGO) protein family. Amplification of Viral siRNAs by a host RNA-dependent RNA polymerase (RdRP) has an essential role in RNA-based antiViral Immunity in plants. Distinct families of cellular RdRPs are conserved in all eukaryotes. Recent deep sequencing has identified siRNA-like virus-derived small RNAs in mammalian cells infected with distinct RNA viruses. However, it is not clear whether these Viral small RNAs function in RNA-based Viral Immunity or other aspects of Viral Immunity and pathogenesis. Many nucleus-replicating DNA viruses that infect vertebrates and invertebrates encode up to 25 microRNAs (miRNAs) to regulate the expression of Viral and host genes implicated in Viral Immunity and pathogenesis. The recent discovery of virus-derived Piwi-interacting RNAs (piRNAs) in infected Drosophila melanogaster cells, which are larger than the 21-nucleotide Viral siRNAs, suggests that piRNAs might have a novel antiViral function in addition to their role in genome defence against transposons and repeat elements. Virus infection in a wide range of eukaryotic host species results in the production of virus-derived small RNAs (such as small interfering RNAs) that specifically target the virus genome through RNA interference and related RNA silencing mechanisms. In this manner, virus-derived small RNAs mediate a form of antiViral Immunity.
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Viral Suppressors of RNA-Based Viral Immunity: Host Targets
Cell Host & Microbe, 2010Co-Authors: Qingfa Wu, Xianbing Wang, Shou-wei DingAbstract:RNA-based Viral Immunity (RVI) operates in fungi, plants, and invertebrates to specifically destroy Viral RNAs using the cellular RNA interference machinery. Discovery of diverse Viral proteins as suppressors of RNA silencing provides strong validation for the effectiveness of RVI. Here we review recent studies that have revealed new mechanistic insights into plant and insect Viral suppressors of RVI or suggested a role for RNA silencing suppression during mammalian Viral infection.
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RNAi-mediated Viral Immunity requires amplification of virus-derived siRNAs in Arabidopsis thaliana
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Xianbing Wang, Takao Ito, Fabrizio Cillo, Xuemei Chen, Shou-wei DingAbstract:In diverse eukaryotic organisms, Dicer-processed, virus-derived small interfering RNAs direct antiViral Immunity by RNA silencing or RNA interference. Here we show that in addition to core dicing and slicing components of RNAi, the RNAi-mediated Viral Immunity in Arabidopsis thaliana requires host RNA-directed RNA polymerase (RDR) 1 or RDR6 to produce Viral secondary siRNAs following Viral RNA replication-triggered biogenesis of primary siRNAs. We found that the two antiViral RDRs exhibited specificity in targeting the tripartite positive-strand RNA genome of cucumber mosaic virus (CMV). RDR1 preferentially amplified the 5′-terminal siRNAs of each of the three Viral genomic RNAs, whereas an increased production of siRNAs targeting the 3′ half of RNA3 detected in rdr1 mutant plants appeared to be RDR6-dependent. However, siRNAs derived from a single-stranded 336-nucleotide satellite RNA of CMV were not amplified by either antiViral RDR, suggesting avoidance of the potent RDR-dependent silencing as a strategy for the molecular parasite of CMV to achieve preferential replication. Our work thus identifies a distinct mechanism for the amplification of Immunity effectors, which together with the requirement for the biogenesis of endogenous siRNAs, may play a role in the emergence and expansion of eukaryotic RDRs.
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RNA-based Viral Immunity initiated by the Dicer family of host immune receptors
Immunological reviews, 2009Co-Authors: Roghiyh Aliyari, Shou-wei DingAbstract:Suppression of Viral infection by RNA in a nucleotide sequence homology-dependent manner was first reported in plants in early 1990s. Studies in the past 15 years have established a completely new RNA-based immune system against viruses that is mechanistically Riverside, CA, USA. related to RNA silencing or RNA interference (RNAi). This Viral Immunity begins with recognition of Viral double-stranded or structured RNA by the Dicer nuclease family of host immune receptors. In fungi, plants and invertebrates, the Viral RNA trigger is processed into small interfering RNAs (siRNAs) to direct specific silencing of the homologous Viral genomic and/or messenger RNAs by an RNaseH-like Argonaute protein. Deep sequencing of virus-derived siRNAs indicates that the Immunity against viruses with a positive-strand RNA genome is induced by Dicer recognition of dsRNA formed during the initiation of Viral progeny (+)RNA synthesis. The RNA-based immune pathway in these organisms overlaps the canonical dsRNA-siRNA pathway of RNAi and may require amplification of Viral siRNAs by host RNA-dependent RNA polymerase in plants and nematodes. Production of virus-derived small RNAs is undetectable in mammalian cells infected with RNA viruses. However, infection of mammals with several nucleus-replicating DNA viruses induces production of virus-derived microRNAs capable of silencing host and Viral mRNAs as found for Viral siRNAs. Remarkably, recent studies indicate that prokaryotes also produce virus-derived small RNAs known as CRISPR RNAs to guide antiViral defense in a manner that has yet to be defined. In this article, we review the recent progress on the identification and mechanism of the key components including Viral sensors, Viral triggers, effectors, and amplifiers, of the small RNA-directed Viral Immunity. We also highlight some of the many unresolved questions.
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rna interference directs innate Immunity against viruses in adult drosophila
Science, 2006Co-Authors: Xiaohong Wang, Roghiyh Aliyari, Kevin Kim, Richard W Carthew, Peter W Atkinson, Shou-wei DingAbstract:Innate Immunity against bacterial and fungal pathogens is mediated by Toll and immune deficiency (Imd) pathways, but little is known about the antiViral response in Drosophila. Here, we demonstrate that an RNA interference pathway protects adult flies from infection by two evolutionarily diverse viruses. Our work also describes a molecular framework for the Viral Immunity, in which Viral double-stranded RNA produced during infection acts as the pathogen trigger whereas Drosophila Dicer-2 and Argonaute-2 act as host sensor and effector, respectively. These findings establish a Drosophila model for studying the innate Immunity against viruses in animals.
Robert B. Darnell - One of the best experts on this subject based on the ideXlab platform.
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ZFP36 RNA-binding proteins restrain T cell activation and anti-Viral Immunity.
eLife, 2018Co-Authors: Michael J. Moore, Nathalie E. Blachere, John J. Fak, Christopher Y. Park, Kirsty Sawicka, Salina Parveen, Ilana Zucker-scharff, Bruno Moltedo, Alexander Y. Rudensky, Robert B. DarnellAbstract:Dynamic post-transcriptional control of RNA expression by RNA-binding proteins (RBPs) is critical during immune response. ZFP36 RBPs are prominent inflammatory regulators linked to autoImmunity and cancer, but functions in adaptive Immunity are less clear. We used HITS-CLIP to define ZFP36 targets in mouse T cells, revealing unanticipated actions in regulating T-cell activation, proliferation, and effector functions. Transcriptome and ribosome profiling showed that ZFP36 represses mRNA target abundance and translation, notably through novel AU-rich sites in coding sequence. Functional studies revealed that ZFP36 regulates early T-cell activation kinetics cell autonomously, by attenuating activation marker expression, limiting T cell expansion, and promoting apoptosis. Strikingly, loss of ZFP36 in vivo accelerated T cell responses to acute Viral infection and enhanced anti-Viral Immunity. These findings uncover a critical role for ZFP36 RBPs in restraining T cell expansion and effector functions, and suggest ZFP36 inhibition as a strategy to enhance immune-based therapies.
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ZFP36 RNA-binding proteins restrain T-cell activation and anti-Viral Immunity
2018Co-Authors: Michael J. Moore, Nathalie E. Blachere, John J. Fak, Christopher Y. Park, Kirsty Sawicka, Salina Parveen, Ilana Zucker-scharff, Bruno Moltedo, Alexander Y. Rudensky, Robert B. DarnellAbstract:Dynamic post-transcriptional control of RNA expression by RNA-binding proteins (RBPs) is critical during immune response. ZFP36 RBPs are prominent inflammatory regulators linked to autoImmunity and cancer, but functions in adaptive Immunity are less clear. We used HITS-CLIP to define ZFP36 targets in T-cells, which revealed unanticipated actions in regulating T-cell activation, proliferation, and effector functions. Transcriptome and ribosome profiling showed that ZFP36 represses mRNA target abundance and translation, notably through a novel class of AU-rich sites in coding sequence. Functional studies revealed that ZFP36 regulates early T-cell activation kinetics in a cell autonomous manner, by attenuating activation marker expression, limiting T-cell expansion, and promoting apoptosis. Strikingly, loss of ZFP36 in vivo accelerated T-cell responses to acute Viral infection, and enhanced anti-Viral Immunity. These findings uncover a critical role for ZFP36 RBPs in restraining T-cell expansion and effector functions, and suggest ZFP36 inhibition as a novel strategy to enhance immune-based therapies.
Michael J. Moore - One of the best experts on this subject based on the ideXlab platform.
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ZFP36 RNA-binding proteins restrain T cell activation and anti-Viral Immunity.
eLife, 2018Co-Authors: Michael J. Moore, Nathalie E. Blachere, John J. Fak, Christopher Y. Park, Kirsty Sawicka, Salina Parveen, Ilana Zucker-scharff, Bruno Moltedo, Alexander Y. Rudensky, Robert B. DarnellAbstract:Dynamic post-transcriptional control of RNA expression by RNA-binding proteins (RBPs) is critical during immune response. ZFP36 RBPs are prominent inflammatory regulators linked to autoImmunity and cancer, but functions in adaptive Immunity are less clear. We used HITS-CLIP to define ZFP36 targets in mouse T cells, revealing unanticipated actions in regulating T-cell activation, proliferation, and effector functions. Transcriptome and ribosome profiling showed that ZFP36 represses mRNA target abundance and translation, notably through novel AU-rich sites in coding sequence. Functional studies revealed that ZFP36 regulates early T-cell activation kinetics cell autonomously, by attenuating activation marker expression, limiting T cell expansion, and promoting apoptosis. Strikingly, loss of ZFP36 in vivo accelerated T cell responses to acute Viral infection and enhanced anti-Viral Immunity. These findings uncover a critical role for ZFP36 RBPs in restraining T cell expansion and effector functions, and suggest ZFP36 inhibition as a strategy to enhance immune-based therapies.
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ZFP36 RNA-binding proteins restrain T-cell activation and anti-Viral Immunity
2018Co-Authors: Michael J. Moore, Nathalie E. Blachere, John J. Fak, Christopher Y. Park, Kirsty Sawicka, Salina Parveen, Ilana Zucker-scharff, Bruno Moltedo, Alexander Y. Rudensky, Robert B. DarnellAbstract:Dynamic post-transcriptional control of RNA expression by RNA-binding proteins (RBPs) is critical during immune response. ZFP36 RBPs are prominent inflammatory regulators linked to autoImmunity and cancer, but functions in adaptive Immunity are less clear. We used HITS-CLIP to define ZFP36 targets in T-cells, which revealed unanticipated actions in regulating T-cell activation, proliferation, and effector functions. Transcriptome and ribosome profiling showed that ZFP36 represses mRNA target abundance and translation, notably through a novel class of AU-rich sites in coding sequence. Functional studies revealed that ZFP36 regulates early T-cell activation kinetics in a cell autonomous manner, by attenuating activation marker expression, limiting T-cell expansion, and promoting apoptosis. Strikingly, loss of ZFP36 in vivo accelerated T-cell responses to acute Viral infection, and enhanced anti-Viral Immunity. These findings uncover a critical role for ZFP36 RBPs in restraining T-cell expansion and effector functions, and suggest ZFP36 inhibition as a novel strategy to enhance immune-based therapies.
Astrid M. Westendorf - One of the best experts on this subject based on the ideXlab platform.
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Combination of nanoparticle-based therapeutic vaccination and transient ablation of regulatory T cells enhances anti-Viral Immunity during chronic retroViral infection
Retrovirology, 2016Co-Authors: Torben Knuschke, Olga Rotan, Wibke Bayer, Viktoriya Sokolova, Wiebke Hansen, Tim Sparwasser, Ulf Dittmer, Matthias Epple, Jan Buer, Astrid M. WestendorfAbstract:Background Regulatory T cells (Tregs) have been shown to limit anti-Viral Immunity during chronic retroViral infection and to restrict vaccine-induced T cell responses. The objective of the study was to assess whether a combinational therapy of nanoparticle-based therapeutic vaccination and concomitant transient ablation of Tregs augments anti-Viral Immunity and improves virus control in chronically retrovirus-infected mice. Therefore, chronically Friend retrovirus (FV)-infected mice were immunized with calcium phosphate (CaP) nanoparticles functionalized with TLR9 ligand CpG and CD8^+ or CD4^+ T cell epitope peptides (GagL_85–93 or Env gp70_123–141) of FV. In addition, Tregs were ablated during the immunization process. Reactivation of CD4^+ and CD8^+ effector T cells was analysed and the Viral loads were determined. Results Therapeutic vaccination of chronically FV-infected mice with functionalized CaP nanoparticles transiently reactivated cytotoxic CD8^+ T cells and significantly reduced the Viral loads. Transient ablation of Tregs during nanoparticle-based therapeutic vaccination strongly enhanced anti-Viral Immunity and further decreased Viral burden. Conclusion Our data illustrate a crucial role for CD4^+ Foxp3^+ Tregs in the suppression of anti-Viral T cell responses during therapeutic vaccination against chronic retroViral infection. Thus, the combination of transient Treg ablation and therapeutic nanoparticle-based vaccination confers robust and sustained anti-Viral Immunity.
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Combination of nanoparticle-based therapeutic vaccination and transient ablation of regulatory T cells enhances anti-Viral Immunity during chronic retroViral infection
Retrovirology, 2016Co-Authors: Torben Knuschke, Olga Rotan, Wibke Bayer, Viktoriya Sokolova, Wiebke Hansen, Tim Sparwasser, Ulf Dittmer, Matthias Epple, Jan Buer, Astrid M. WestendorfAbstract:Background Regulatory T cells (Tregs) have been shown to limit anti-Viral Immunity during chronic retroViral infection and to restrict vaccine-induced T cell responses. The objective of the study was to assess whether a combinational therapy of nanoparticle-based therapeutic vaccination and concomitant transient ablation of Tregs augments anti-Viral Immunity and improves virus control in chronically retrovirus-infected mice. Therefore, chronically Friend retrovirus (FV)-infected mice were immunized with calcium phosphate (CaP) nanoparticles functionalized with TLR9 ligand CpG and CD8+ or CD4+ T cell epitope peptides (GagL85–93 or Env gp70123–141) of FV. In addition, Tregs were ablated during the immunization process. Reactivation of CD4+ and CD8+ effector T cells was analysed and the Viral loads were determined.
Xianbing Wang - One of the best experts on this subject based on the ideXlab platform.
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Viral Suppressors of RNA-Based Viral Immunity: Host Targets
Cell Host & Microbe, 2010Co-Authors: Qingfa Wu, Xianbing Wang, Shou-wei DingAbstract:RNA-based Viral Immunity (RVI) operates in fungi, plants, and invertebrates to specifically destroy Viral RNAs using the cellular RNA interference machinery. Discovery of diverse Viral proteins as suppressors of RNA silencing provides strong validation for the effectiveness of RVI. Here we review recent studies that have revealed new mechanistic insights into plant and insect Viral suppressors of RVI or suggested a role for RNA silencing suppression during mammalian Viral infection.
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RNAi-mediated Viral Immunity requires amplification of virus-derived siRNAs in Arabidopsis thaliana
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Xianbing Wang, Takao Ito, Fabrizio Cillo, Xuemei Chen, Shou-wei DingAbstract:In diverse eukaryotic organisms, Dicer-processed, virus-derived small interfering RNAs direct antiViral Immunity by RNA silencing or RNA interference. Here we show that in addition to core dicing and slicing components of RNAi, the RNAi-mediated Viral Immunity in Arabidopsis thaliana requires host RNA-directed RNA polymerase (RDR) 1 or RDR6 to produce Viral secondary siRNAs following Viral RNA replication-triggered biogenesis of primary siRNAs. We found that the two antiViral RDRs exhibited specificity in targeting the tripartite positive-strand RNA genome of cucumber mosaic virus (CMV). RDR1 preferentially amplified the 5′-terminal siRNAs of each of the three Viral genomic RNAs, whereas an increased production of siRNAs targeting the 3′ half of RNA3 detected in rdr1 mutant plants appeared to be RDR6-dependent. However, siRNAs derived from a single-stranded 336-nucleotide satellite RNA of CMV were not amplified by either antiViral RDR, suggesting avoidance of the potent RDR-dependent silencing as a strategy for the molecular parasite of CMV to achieve preferential replication. Our work thus identifies a distinct mechanism for the amplification of Immunity effectors, which together with the requirement for the biogenesis of endogenous siRNAs, may play a role in the emergence and expansion of eukaryotic RDRs.
