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Project description:Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that causes severe outbreaks in human populations. ZIKV infection leads to the accumulation of small non-coding viral RNAs (known as sfRNAs) that are crucial for evasion of antiviral responses and for viral pathogenesis. However, the mechanistic understanding of how sfRNAs function remains incomplete. Here, we use recombinant ZIKVs and ribosome profiling of infected human cells to show that sfRNAs block translation of antiviral genes. Mechanistically, we demonstrate that specific RNA structures present in sfRNAs trigger PKR activation, which instead of limiting viral replication, enhances viral particle production. Although ZIKV infection induces mRNA expression of antiviral genes, translation efficiency of type I interferon and interferon stimulated genes were significantly downregulated by PKR activation. Our results reveal a novel viral adaptation mechanism mediated by sfRNAs, where ZIKV increases its fitness by repurposing the antiviral role of PKR into a proviral factor.
2024-04-28 | GSE254253 | GEO
Project description:Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that causes severe outbreaks in human populations. ZIKV infection leads to the accumulation of small non-coding viral RNAs (known as sfRNAs) that are crucial for evasion of antiviral responses and for viral pathogenesis. However, the mechanistic understanding of how sfRNAs function remains incomplete. Here, we use recombinant ZIKVs and ribosome profiling of infected human cells to show that sfRNAs block translation of antiviral genes. Mechanistically, we demonstrate that specific RNA structures present in sfRNAs trigger PKR activation, which instead of limiting viral replication, enhances viral particle production. Although ZIKV infection induces mRNA expression of antiviral genes, translation efficiency of type I interferon and interferon stimulated genes were significantly downregulated by PKR activation. Our results reveal a novel viral adaptation mechanism mediated by sfRNAs, where ZIKV increases its fitness by repurposing the antiviral role of PKR into a proviral factor.
2024-04-28 | GSE254252 | GEO
Project description:Zika Virus Non-Coding RNAs Antagonize Antiviral Responses by PKR-Mediated Translational Arrest
| PRJNA1069079 | ENA
Project description:Zika Virus Non-Coding RNAs Antagonize Antiviral Responses by PKR-Mediated Translational Arrest (RNA-Seq)
| PRJNA1069084 | ENA
Project description:Zika Virus Non-Coding RNAs Antagonize Antiviral Responses by PKR-Mediated Translational Arrest (Ribo-Seq)
| PRJNA1069085 | ENA
Project description:NLRX1 is unique among the nucleotide-binding-domain and leucine-rich-repeat (NLR) proteins in its mitochondrial localization and ability to negatively regulate antiviral innate immunity dependent on the adaptors MAVS and STING. However, some studies have suggested a positive regulatory role for NLRX1 in inducing antiviral responses. We found that NLRX1 exerted opposing regulatory effects on viral activation of the transcription factors IRF1 and IRF3, which might potentially explain such contradictory results. Whereas NLRX1 suppressed MAVS-mediated activation of IRF3, it conversely facilitated virus-induced increases in IRF1 expression and thereby enhanced control of viral infection. NLRX1 had a minimal effect on the transcription of IRF1 mediated by the transcription factor NF-kB and regulated the abundance of IRF1 post-transcriptionally by preventing translational shutdown mediated by the double-stranded RNA (dsRNA)-activated kinase PKR and thereby allowed virus-induced increases in the abundance of IRF1 protein.
| S-EPMC5690873 | biostudies-literature
Project description:The mechanisms by which flaviviruses use non-canonical translation to support their replication in host cells are largely unknown. Here, we investigated how the integrated stress response (ISR), which promotes translational arrest by eIF2ɑ phosphorylation (p-eIF2ɑ), regulates flavivirus replication. During dengue virus (DENV) and Zika virus (ZIKV) infection, eIF2ɑ phosphorylation peaked at 24 hours post-infection and was dependent on protein kinase RNA-activated (PKR) but not type I interferon. The ISR is activated downstream of p-eIF2α during infection with either virus, but translation arrest only occurred following DENV4 infection. Despite this difference, both DENV4 and ZIKV replications were impaired in cells lacking PKR, independent of type I interferon/NF-kB signaling or cell viability. By using a ZIKV 5'-untranslated region (UTR) reporter system as a model, we found that this region of the genome is sufficient to promote an enhancement of viral mRNA translation in the presence of an active ISR. Together, we provide evidence that flaviviruses escape ISR translational arrest and co-opt this response to increase viral replication. IMPORTANCE One of the fundamental features that make viruses intracellular parasites is the necessity to use cellular translational machinery. Hence, this is a crucial checkpoint for controlling infections. Here, we show that dengue and Zika viruses, responsible for nearly 400 million infections every year worldwide, explore such control for optimal replication. Using immunocompetent cells, we demonstrate that arrest of protein translations happens after sensing of dsRNA and that the information required to avoid this blocking is contained in viral 5'-UTR. Our work, therefore, suggests that the non-canonical translation described for these viruses is engaged when the intracellular stress response is activated.
| S-EPMC10653888 | biostudies-literature
Project description:Genome-wide investigations of host-pathogen interactions are often limited by analyses of mixed populations of infected and uninfected cells, which lower sensitivity and accuracy. To overcome these obstacles and identify key mechanisms by which Zika virus (ZIKV) manipulates host responses, we developed a system that enables simultaneous characterization of genome-wide transcriptional and epigenetic changes in ZIKV-infected and neighboring uninfected primary human macrophages. We demonstrate that transcriptional responses in ZIKV-infected macrophages differed radically from those in uninfected neighbors and that studying the cell population as a whole produces misleading results. Notably, the uninfected population of macrophages exhibits the most rapid and extensive changes in gene expression, related to type I IFN signaling. In contrast, infected macrophages exhibit a delayed and attenuated transcriptional response distinguished by preferential expression of IFNB1 at late time points. Biochemical and genomic studies of infected macrophages indicate that ZIKV infection causes both a targeted defect in the type I IFN response due to degradation of STAT2 and reduces RNA polymerase II protein levels and DNA occupancy, particularly at genes required for macrophage identity. Simultaneous evaluation of transcriptomic and epigenetic features of infected and uninfected macrophages thereby reveals the coincident evolution of dominant proviral or antiviral mechanisms, respectively, that determine the outcome of ZIKV exposure.
| S-EPMC6166801 | biostudies-literature
Project description:Flavivirus genus includes numerous arthropod-borne human pathogens that are clinically important. Flaviviruses are notorious for their ability to antagonize host interferon (IFN) induced anti-viral signalling. It has been documented that NS5s of flaviviruses mediate proteasome degradation of STAT2 to evade IFN signalling. Deciphering the molecular mechanism of the IFN antagonism by the viruses and reversing this antagonism may dictate anti-viral responses and provide novel antiviral approaches. In this report, by using Zika virus (ZIKV) as a model, we first demonstrated that ZIKV antagonized interferon signalling in an infectious dose-dependent manner; in other words, the virus antagonized interferon signalling at a high multiple of infection (MOI) and was sensitive to interferon signalling at a low MOI. Mechanistically, we found that ZIKV infection triggered degradation of ubiquitinated STAT2 and host short-lived proteins while didn't affect the proteasome activity per se. ZIKV infection resulted in suppression of host de novo protein synthesis. Overexpression of NS5 alone only marginally reduced STAT2 and had no effect on the host de novo protein synthesis. Ectopically expressed murine STAT2 that was resistant to NS5- and ZIKV-induced ablation exaggerated the IFN-induced anti-viral signalling. These data favour a new model of the innate immune evasion of ZIKV in which the viral infection triggers suppression of host de novo protein synthesis to accelerate the degradation of short-lived, ubiquitinated STAT2. As flaviviruses share a very conserved replication strategy, the mechanisms of IFN antagonism elucidated here might also be employed by other flaviviruses.
| S-EPMC8366623 | biostudies-literature
Project description:Seneca Valley virus (SVV) is a new pathogen associated with porcine idiopathic vesicular disease (PIVD) in recent years. However, SVV-host interaction is still unclear. In this study, through LC-MS/MS analysis and coimmunoprecipitation analysis, DHX30 was identified as a 3Cpro-interacting protein. 3Cpro mediated the cleavage of DHX30 at a specific site, which depends on its protease activity. Further study showed that DHX30 was an intrinsic antiviral factor against SVV that was dependent on its helicase activity. DHX30 functioned as a viral-RNA binding protein that inhibited SVV replication at the early stage of viral infection. RIP-seq showed comparatively higher coverage depth at SVV 5'UTR, but the distribution across SVV RNA suggested that the interaction had low specificity. DHX30 expression strongly inhibited double-stranded RNA (dsRNA) production. Interestingly, DHX30 was determined to interact with 3D in an SVV RNA-dependent manner. Thus, DHX30 negatively regulated SVV propagation by blocking viral RNA synthesis, presumably by participating in the viral replication complex. IMPORTANCE DHX30, an RNA helicase, is identified as a 3Cpro-interacting protein regulating Seneca Valley virus (SVV) replication dependent on its helicase activity. DHX30 functioned as a viral-RNA binding protein that inhibited SVV replication at the early stage of virus infection. DHX30 expression strongly inhibited double-stranded RNA (dsRNA) production. In addition, 3Cpro abolished DHX30 antiviral effects by inducing DHX30 cleavage. Thus, DHX30 is an intrinsic antiviral factor that inhibits SVV replication.
| S-EPMC9472649 | biostudies-literature