Reply to ‘Questioning antiviral RNAi in mammals’

Jeffrey, Kate L.; Li, Yang; Ding, Shou‐Wei

doi:10.1038/nmicrobiol.2017.53

Cited by 12 publications

(11 citation statements)

References 33 publications

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“…RNAi‐based approaches to antiviral therapy show both promise and new and familiar challenges. Most known primate‐infective viruses manipulate IFN signalling; however, despite nearly two decades of study, the role of RNAi as a specific immune defence mechanism in somatic, IFN‐responsive tissues remains controversial . If IFN‐ and RNAi‐mediated immunity are incompatible, human‐infective viruses would likely be subjected to only weak, if any, specific RNAi‐mediated immune selective pressure.…”

Section: Challenges and Strategies In Targeting Multifunctional Host mentioning

confidence: 99%

Harnessing host–virus evolution in antiviral therapy and immunotherapy

Heaton

2019

Clin & Trans Imm

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Pathogen resistance and development costs are major challenges in current approaches to antiviral therapy. The high error rate of RNA synthesis and reverse‐transcription confers genome plasticity, enabling the remarkable adaptability of RNA viruses to antiviral intervention. However, this property is coupled to fundamental constraints including limits on the size of information available to manipulate complex hosts into supporting viral replication. Accordingly, RNA viruses employ various means to extract maximum utility from their informationally limited genomes that, correspondingly, may be leveraged for effective host‐oriented therapies. Host‐oriented approaches are becoming increasingly feasible because of increased availability of bioactive compounds and recent advances in immunotherapy and precision medicine, particularly genome editing, targeted delivery methods and RNAi. In turn, one driving force behind these innovations is the increasingly detailed understanding of evolutionarily diverse host–virus interactions, which is the key concern of an emerging field, neo‐virology. This review examines biotechnological solutions to disease and other sustainability issues of our time that leverage the properties of RNA and DNA viruses as developed through co‐evolution with their hosts.

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Section: Challenges and Strategies In Targeting Multifunctional Host mentioning

confidence: 99%

Harnessing host–virus evolution in antiviral therapy and immunotherapy

Heaton

2019

Clin & Trans Imm

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“…Recently, a number of studies have started to question whether the primordial antiviral function of RNAi has truly been abandoned by mammalian cells or whether it can constitute a physiologically relevant antiviral system that complements the IFN pathway. This has become an area of controversy, with some investigators suggesting that RNAi can be a relevant means of cell‐intrinsic restriction to virus infection in mammals while others argue that it is an epiphenomenon with no role in antiviral resistance (Cullen et al, ; Cullen, ; Ding & Voinnet, ; tenOever, , ; Jeffrey et al, ). In this review, we address this controversy and summarise current understanding of antiviral RNAi pathways in mammals and reflect on the possible contexts in which it might play a role.…”

Section: Introductionmentioning

confidence: 99%

Slicing and dicing viruses: antiviral RNA interference in mammals

et al. 2019

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To protect against the harmful consequences of viral infections, organisms are equipped with sophisticated antiviral mechanisms, including cell‐intrinsic means to restrict viral replication and propagation. Plant and invertebrate cells utilise mostly RNA interference ( RNA i), an RNA ‐based mechanism, for cell‐intrinsic immunity to viruses while vertebrates rely on the protein‐based interferon ( IFN )‐driven innate immune system for the same purpose. The RNA i machinery is conserved in vertebrate cells, yet whether antiviral RNA i is still active in mammals and functionally relevant to mammalian antiviral defence is intensely debated. Here, we discuss cellular and viral factors that impact on antiviral RNA i and the contexts in which this system might be at play in mammalian resistance to viral infection.

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“…All components of the RNAi pathway are conserved in mammals, and siRNA-based gene silencing is frequently exploited as an experimental tool in mammalian cells. However, Dicer's catalytic function appears mainly confined to precursor microRNA (pre-miRNA) processing, and its antiviral capacity in mammals remains much debated (Parameswaran et al, 2010;Cullen et al, 2013;Li et al, 2013Li et al, , 2016Maillard et al, 2013;Backes et al, 2014;Ding & Voinnet, 2014;Kennedy et al, 2015;Jeffrey et al, 2017;tenOever, 2017). Some studies have reported that RNAi can impact antiviral immunity in mammals during influenza A virus, hepatitis C virus, Nodamura virus and, more recently, human enterovirus 71 infection (Wang et al, 2006;Matskevich & Moelling, 2007;Li et al, 2013Li et al, , 2016Maillard et al, 2013;Qiu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

et al. 2018

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In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG‐I‐like receptor (RLR) family, which signal to induce production of type I interferons (IFN). These key antiviral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon‐stimulated genes (ISGs), whose protein products restrict viral entry, replication and budding. ISGs include the RLRs themselves: RIG‐I, MDA5 and, the least‐studied family member, LGP2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference (RNAi). In RNAi, the endoribonuclease Dicer cleaves virus‐derived double‐stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that target complementary viral RNA for cleavage. Interestingly, the RNAi machinery is conserved in mammals, and we have recently demonstrated that it is able to participate in mammalian antiviral defence in conditions in which the IFN system is suppressed. In contrast, when the IFN system is active, one or more ISGs act to mask or suppress antiviral RNAi. Here, we demonstrate that LGP2 constitutes one of the ISGs that can inhibit antiviral RNAi in mammals. We show that LGP2 associates with Dicer and inhibits cleavage of dsRNA into siRNAs both in vitro and in cells. Further, we show that in differentiated cells lacking components of the IFN response, ectopic expression of LGP2 interferes with RNAi‐dependent suppression of gene expression. Conversely, genetic loss of LGP2 uncovers dsRNA‐mediated RNAi albeit less strongly than complete loss of the IFN system. Thus, the inefficiency of RNAi as a mechanism of antiviral defence in mammalian somatic cells can be in part attributed to Dicer inhibition by LGP2 induced by type I IFNs. LGP2‐mediated antagonism of dsRNA‐mediated RNAi may help ensure that viral dsRNA substrates are preserved in order to serve as targets of antiviral ISG proteins.

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Reply to ‘Questioning antiviral RNAi in mammals’

Cited by 12 publications

References 33 publications

Harnessing host–virus evolution in antiviral therapy and immunotherapy

Harnessing host–virus evolution in antiviral therapy and immunotherapy

Slicing and dicing viruses: antiviral RNA interference in mammals

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

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