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Enoxacin shows a broad-spectrum antiviral activity against diverse viruses by enhancing antiviral RNAi in insects

ABSTRACT: RNA interference (RNAi) functions as the major host antiviral defense in insects, while less is understood about how to utilize antiviral RNAi in controlling viral infection in insects. Enoxacin belongs to the family of synthetic antibacterial compounds based on a fluoroquinolone skeleton that has been previously found to enhance RNAi in mammalian cells. In this study, we showed that enoxacin efficiently inhibited viral replication of Drosophila C virus (DCV) and Cricket paralysis virus (CrPV) in cultured Drosophila cells. Enoxacin promoted the loading of Dicer-2-processed virus-derived siRNA into the RNA-induced silencing complex, thereby enhancing antiviral RNAi response in infected cells. Moreover, enoxacin treatment elicited an RNAi-dependent in vivo protective efficacy against DCV or CrPV challenge in adult fruit flies. In addition, enoxacin also inhibited replication of flaviviruses, including Dengue virus and Zika virus, in Aedes mosquito cells in an RNAi-dependent manner. Together, our findings demonstrated that enoxacin can enhance RNAi in insects, and enhancing RNAi by enoxacin is an effective antiviral strategy against diverse viruses in insects, which may be exploited as a broad-spectrum antiviral agent to control vector transmission of arboviruses or viral diseases in insect farming.

ORGANISM(S): Drosophila C virus strain EB Drosophila melanogaster

PROVIDER: GSE189204 | GEO | 2021/11/22

REPOSITORIES: GEO

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A Dicistrovirus-specific inducible antiviral response in Drosophila

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2013-02-06 | E-GEOD-31542 | biostudies-arrayexpress

A Dicistrovirus-specific inducible antiviral response in Drosophila

2013-02-06 | GSE31542 | GEO

Alphavirus infection triggers antiviral RNAi immunity in mammals

Project description:RNA interference (RNAi) functions as an antiviral immune response in plants and invertebrates, whereas mammalian RNAi response has been found so far only in undifferentiated cells and in differentiated cells inactive in interferon (IFN) system or in infections with viruses disabling viral suppressors of RNAi (VSRs), thereby leading to question the physiological importance of the RNAi pathway in mammals. Here, we identified that wild-type Semliki Forest virus (SFV), a prototypic alphavirus, triggered the Dicer-dependent production of abundant viral (v)siRNAs in different mammalian somatic cells in the presence of VSR. These vsiRNAs were produced from viral dsRNA replicative intermediates, almost exclusively located at the 5’ termini of the viral genome, and loaded into AGO, and they were fully active in slicing cognate viral RNAs. Besides, Sindbis virus, another alphavirus, also induced vsiRNA generation in mammalian somatic cells. AGO2 deficiency increased SFV and SINV replication, while enoxacin, a known RNAi enhancer that functions at post steps of siRNA production, efficiently reduced viral replication. The nucleotide sequence at the 5’ termini of SFV and SINV genome is conserved among the Old World alphaviruses, and mutating the conserved sequences resulted in the recombinant SFV being deficient in vsiRNA production and irresponsive to antiviral RNAi. SFV infection also enabled the production of abundant vsiRNAs and antiviral RNAi in IFN-competent adult mice, and importantly, enhanced RNAi by enoxacin protected adult mice from lethal SFV challenge and reduced the virus-induced neuropathogenesis in the central neuron system. Overall, our findings provide evidence that mammalian antiviral RNAi is active in differentiated cells and adult mice with intact IFN response even in the presence of VSR and present a therapeutic strategy against alphaviruses that include many important emerging and reemerging human pathogens.

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Enoxacin shows a broad-spectrum antiviral activity against diverse viruses by enhancing antiviral RNAi in insects

Project description:Enoxacin shows a broad-spectrum antiviral activity against diverse viruses by enhancing antiviral RNAi in insects

| PRJNA781957 | ENA

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2013-10-10 | E-GEOD-43153 | biostudies-arrayexpress

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2013-10-10 | GSE43153 | GEO

STUB1 regulates antiviral RNAi through inducing ubiquitination and degradation of Dicer and AGO2 in mammals

Project description:RNA interference (RNAi) is a cell-intrinsic antiviral defense conserved in diverse organisms. However, the mechanism by which mammalian antiviral RNAi is regulated is largely unknown. Herein, we uncover that STUB1, an E3 ubiquitin ligase, interacts with and ubiquitinates AGO2, the core component of RNAi pathway, resulting in the degradation of AGO2 via ubiquitin-proteasome system. Additionally, STUB1 can induce the degradation of the other mammalian AGO proteins including AGO1, AGO3, and AGO4. Our further study reveals that STUB1 also interacts with and mediates the ubiquitination of Dicer, the endoribonuclease responsible for siRNA or miRNA biogenesis, via K48-linked poly-ubiquitin, which induces the degradation of Dicer and its specialized form, termed antiviral Dicer (aviDicer) that usually expresses in stem cells. Loss of STUB1 upregulated Dicer and AGO2, thereby enhancing antiviral RNAi to effectively inhibit viral RNA replication in mammalian cells. In vivo, the STUB1 deficiency markedly enhanced the production of virus-derived siRNAs and elicited a potent antiviral effect against Enterovirus-A71 (EV-A71) infection in newborn mouse. Our findings demonstrate STUB1 as a novel negative regulator of RNAi by mediating the ubiquitination and degradation of Dicer and AGO proteins, and provide novel insights into the regulatory mechanism of antiviral RNAi in mammals.

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