Flavivirus induces and antagonizes antiviral RNA interference in both mammals and mosquitoes

Qiu, Yang; Xu, Yan‐Peng; Wang, Miao; Meng, Mingyao; Zhou, Hui; Xu, Junchao; Kong, Jing; Zheng, Da-Zhong; Li, Rui-Ting; Zhang, Rongrong; Guo, Yan; Li, Xiaofeng; Cui, Jie; Qin, Cheng‐Feng; Zhou, Xi

doi:10.1126/sciadv.aax7989

Cited by 68 publications

(74 citation statements)

References 46 publications

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“…Distinct positive-and negative-strand RNA viruses from the Flaviviridae, Nodaviridae, Orthomyxoviridae, and Picornaviridae induce Dicer-mediated production of vsiRNAs and encode unrelated dsRNA-binding VSRs to suppress the biogenesis of cognate vsiRNAs in mammalian cells (10,(12)(13)(14)(15). Results from this work provide several important insights into the mechanism and function of the new mammalian antiviral response.…”

Section: Discussionmentioning

confidence: 88%

“…Mammalian antiviral RNAi has been documented during infection of either undifferentiated cells with wild-type viruses or differentiated cells and mice with mutant viruses rendered defective in RNAi suppression (10)(11)(12)(13)(14)(15). However, previous studies have shown that a range of wild-type RNA viruses do not trigger production of a dominant peak of vsiRNAs in several commonly used lines of mature mammalian cells or replicate to higher levels in human 293T cells upon Dicer inactivation (15,(54)(55)(56)(57)(58).…”

Section: Discussionmentioning

confidence: 99%

“…In counter defense, Nodamura virus (NoV; Nodaviridae), influenza A virus (IAV; Orthomyxoviridae), human enterovirus 71 (HEV71; Picornaviridae), and dengue virus-2 (DENV2; Flaviviridae) each encode a viral suppressor of RNAi (VSR), designated protein B2, NS1, 3A, and 2A, respectively. These VSRs share no primary sequence similarity, but all act to suppress Dicer processing of the vsiRNA precursors as dsRNA-binding proteins (10,(12)(13)(14)(15). Thus, when VSR is rendered nonexpressing or nonfunctional, the resulting mutant viruses induce abundant vsiRNAs, replicate less efficiently than parental viruses in mESCs, mature murine, monkey, and human cells, and/or newborn mice and are efficiently rescued by knocking out all four Ago genes in mESCs or Dicer gene in human 293T cells (10,(12)(13)(14)(15).…”

mentioning

confidence: 99%

“…These VSRs share no primary sequence similarity, but all act to suppress Dicer processing of the vsiRNA precursors as dsRNA-binding proteins (10,(12)(13)(14)(15). Thus, when VSR is rendered nonexpressing or nonfunctional, the resulting mutant viruses induce abundant vsiRNAs, replicate less efficiently than parental viruses in mESCs, mature murine, monkey, and human cells, and/or newborn mice and are efficiently rescued by knocking out all four Ago genes in mESCs or Dicer gene in human 293T cells (10,(12)(13)(14)(15). Moreover, ebolavirus VP35 and the nucleocapsid protein of yellow fever virus (Flaviviridae), Semliki Forest virus (Togaviridae), and severe acute respiratory syndrome coronavirus (SARS CoV) and SARS CoV-2 also display activities of dsRNA-binding VSRs (15, 17-19, 64, 65).…”

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confidence: 99%

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Mechanism and Function of Antiviral RNA Interference in Mice

Han

Chen

Wang

et al. 2020

mBio

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Distinct mammalian RNA viruses trigger Dicer-mediated production of virus-derived small-interfering RNAs (vsiRNA) and encode unrelated proteins to suppress vsiRNA biogenesis. However, the mechanism and function of the mammalian RNA interference (RNAi) response are poorly understood. Here, we characterized antiviral RNAi in a mouse model of infection with Nodamura virus (NoV), a mosquito-transmissible positive-strand RNA virus encoding a known double-stranded RNA (dsRNA)-binding viral suppressor of RNAi (VSR), the B2 protein. We show that inhibition of NoV RNA replication by antiviral RNAi in mouse embryonic fibroblasts (MEFs) requires Dicer-dependent vsiRNA biogenesis and Argonaute-2 slicer activity. We found that VSR-B2 of NoV enhances viral RNA replication in wild-type but not RNAi-defective MEFs such as Argonaute-2 catalytic-dead MEFs and Dicer or Argonaute-2 knockout MEFs, indicating that VSR-B2 acts mainly by suppressing antiviral RNAi in the differentiated murine cells. Consistently, VSR-B2 expression in MEFs has no detectable effect on the induction of interferon-stimulated genes or the activation of global RNA cleavages by RNase L. Moreover, we demonstrate that NoV infection of adult mice induces production of abundant vsiRNA active to guide RNA slicing by Argonaute-2. Notably, VSR-B2 suppresses the biogenesis of both vsiRNA and the slicing-competent vsiRNA-Argonaute-2 complex without detectable inhibition of Argonaute-2 slicing guided by endogenous microRNA, which dramatically enhances viral load and promotes lethal NoV infection in adult mice either intact or defective in the signaling by type I, II, and III interferons. Together, our findings suggest that the mouse RNAi response confers essential protective antiviral immunity in both the presence and absence of the interferon response. IMPORTANCE Innate immune sensing of viral nucleic acids in mammals triggers potent antiviral responses regulated by interferons known to antagonize the induction of RNA interference (RNAi) by synthetic long double-stranded RNA (dsRNA). Here, we show that Nodamura virus (NoV) infection in adult mice activates processing of the viral dsRNA replicative intermediates into small interfering RNAs (siRNAs) active to guide RNA slicing by Argonaute-2. Genetic studies demonstrate that NoV RNA replication in mouse embryonic fibroblasts is inhibited by the RNAi pathway and enhanced by the B2 viral RNAi suppressor only in RNAi-competent cells. When B2 is rendered nonexpressing or nonfunctional, the resulting mutant viruses become nonpathogenic and are cleared in adult mice either intact or defective in the signaling by type I, II, and III interferons. Our findings suggest that mouse antiviral RNAi is active and necessary for the in vivo defense against viral infection in both the presence and absence of the interferon response.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Mechanism and Function of Antiviral RNA Interference in Mice

Han

Chen

Wang

et al. 2020

mBio

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show abstract

“…As a countermeasure, viruses encode viral suppressors of RNAi (VSRs) to antagonize the RNAi pathway at different steps. For example, Influenza A virus (IAV) NS1, human enterovirus A71 (EV-A71) 3A and Dengue virus 2 (DENV2) NS2A have been identified to act as VSRs to inhibit vsiRNA production and antiviral RNAi response in the context of viral infections (Qiu et al, 2020;Ding et al, 2018). Thus, the understanding of how SARS-CoV-2 interacts with antiviral RNAi is important for the better knowledge of this novel coronavirus, and may contribute to the efforts of controlling the spread of infections and developing effective therapies.…”

mentioning

confidence: 99%