MiR-342-5p suppresses coxsackievirus B3 biosynthesis by targeting the 2C-coding region

Wang, Linlin; Qin, Ying; Tong, Lei; Wu, Shuo; Wang, Qiang; Jiao, Qingguo; Guo, Zhiwei; Lin, Lexun; Wang, Ruixue; Zhao, Wenran; Zhong, Zhaohua

doi:10.1016/j.antiviral.2011.12.004

Cited by 68 publications

(58 citation statements)

References 51 publications

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“…Meanwhile, replication of another RNA virus, VSV, can be inhibited by miR-93 and miR-24 (20). Replication of CVB3, which belongs to the same genus as EV71, has been shown to be inhibited by hsa-miR-342-5p (30). Our present work shows that cellular miRNAs can effectively exert antiviral activity during the host immune response to the infection.…”

Section: Discussionmentioning

confidence: 55%

“…Indeed, EV71 has been shown to induce the expression of miRNA-141, which can target the eIF4E translation initiation factor to downregulate host protein synthesis (29). In addition, miR-342-5p suppresses the biosynthesis of coxsackievirus B3 (CVB3), another human enterovirus, by targeting the 2C-coding region on the viral genome (30). Since there is strong evidence that cellular miRNAs can be used by host cells to resist viral infection, it is possible that EV71 replication can be suppressed by host miRNAs.…”

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confidence: 99%

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Human MicroRNA hsa-miR-296-5p Suppresses Enterovirus 71 Replication by Targeting the Viral Genome

Zheng

Wang

et al. 2013

J Virol

164

151

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Enterovirus 71 (EV71) has emerged as a major cause of neurological disease following the near eradication of poliovirus. Accumulating evidence suggests that mammalian microRNAs (miRNAs), a class of noncoding RNAs of 18 to 23 nucleotides (nt) with important regulatory roles in many cellular processes, participate in host antiviral defenses. However, the roles of miRNAs in EV71 infection and pathogenesis are still unclear. Here, hsa-miR-296-5p expression was significantly increased in EV71-infected human cells. As determined by virus titration, quantitative real-time PCR (qRT-PCR), and Western blotting, overexpression of hsa-miR-296-5p inhibited, while inhibition of endogenous hsa-miR-296-5p facilitated, EV71 infection. Additionally, two potential hsa-miR-296-5p targets (nt 2115 to 2135 and nt 2896 to 2920) located in the EV71 genome (strain BrCr) were bioinformatically predicted and validated by luciferase reporter assays and Western blotting. Genomic alignment of various EV71 strains revealed synonymous mutations in hsa-miR-296-5p target sequences. Furthermore, the introduction of synonymous mutations into the EV71 BrCr genome by site-directed mutagenesis impaired the viral inhibitory effects of hsa-miR-296-5p and facilitated mutant virus infection. Meanwhile, compensatory mutations in corresponding hsa-miR-296-5p target sequences of the EV71 HeN strain (GenBank accession number JN256064) restored the inhibitory effects of the miRNA. These results indicate that hsa-miR-296-5p inhibits EV71 replication by targeting the viral genome. Our findings support the notion that cellular miRNAs can inhibit virus infection and that the virus mutates to escape suppression by cellular miRNAs.

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Section: Discussionmentioning

confidence: 55%

mentioning

confidence: 99%

Human MicroRNA hsa-miR-296-5p Suppresses Enterovirus 71 Replication by Targeting the Viral Genome

Zheng

Wang

et al. 2013

J Virol

164

151

View full text Add to dashboard Cite

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“…Previous studies provided evidence to support that miRNAs could modulate viral translation through imperfect or perfect binding to the 3= UTR (24), the 5= UTR (25)(26)(27), or the sequences within the coding region (28)(29)(30). The 5= UTR (7), 3= UTR (11,31,32), or coding position locations (7) selected for miRT insertion differed among various viruses depending upon where insertion was tolerated within the particular virus.…”

Section: Discussionmentioning

confidence: 99%

Coxsackievirus B3 Engineered To Contain MicroRNA Targets for Muscle-Specific MicroRNAs Displays Attenuated Cardiotropic Virulence in Mice

Yao

Wang

et al. 2015

J Virol

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Coxsackievirus B3 (CVB3) is trophic for cardiac tissue and is a major causative agent for viral myocarditis, where local viral replication in the heart may lead to heart failure or even death. Recent studies show that inserting microRNA target sequences into the genomes of certain viruses can eradicate these viruses within local host tissues that specifically express the cognate microRNA. Here, we demonstrated both in vitro and in vivo that incorporating target sequences for miRNA-133 and -206 into the 5= untranslated region of the CVB3 genome ameliorated CVB3 virulence in skeletal muscle and myocardial cells that specifically expressed the cognate cellular microRNAs. Compared to wild-type CVB3, viral replication of the engineered CVB3 was attenuated in human TE671 (rhabdomyosarcoma) and L6 (skeletal muscle) cell lines in vitro that expressed high levels of miRNA-206. In the in vivo murine CVB3-infection model, viral replication of the engineered CVB3 was attenuated specifically in the heart that expressed high levels of both miRNAs, but not in certain tissues, which allowed the host to retain the ability to induce a strong and protective humoral immune response against CVB3. The results of this study suggest that a microRNA-targeting strategy to control CVB3 tissue tropism and pathogenesis may be useful for viral attenuation and vaccine development. IMPORTANCECoxsackievirus B3 (CVB3) is a major causative agent for viral myocarditis, and viral replication in the heart may lead to heart failure or even death. Limiting CVB3 replication within the heart may be a promising strategy to decrease CVB3 pathogenicity. miRNAs are ϳ21-nucleotide-long, tissue-specific endogenous small RNA molecules that posttranscriptionally regulate gene expression by imperfectly binding to the 3= untranslated region (UTR), the 5= UTR, or the coding region within a gene. In our study, muscle-specific miRNA targets (miRT) were incorporated into the CVB3 genome. Replication of the engineered viruses was restricted in the important heart tissue of infected mice, which reduced cardiac pathology and increased mouse survival. Meanwhile, replication ability was retained in other tissues, thus inducing a strong humoral immune response and providing long-term protection against CVB3 rechallenge. This study suggests that a microRNA-targeting strategy can potentially control CVB3 tissue tropism and pathogenesis and may be useful for viral attenuation and vaccine development. C oxsackievirus B3 (CVB3) is a clinically relevant infectious agent that causes viral myocarditis, pancreatitis, and aseptic meningitis. CVB3 is cardiotropic and efficiently replicates in the heart. We and others have shown in various animal models that CVB3 replication induces a direct cytopathic effect on infected cells, leading to tissue damage (1, 2). At present, there is no effective therapy against CVB3, and strategies to develop such a therapy are greatly desired (3, 4). Limiting CVB3 replication within the heart may be a promising strategy to decrease CVB3 pathoge...

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“…While miR-342-5p shows the ability to repress CVB3 replication, miR-10* promotes viral replication. 56,57 In addition to directly targeting the picornaviral genomes, miRNAs can also target the mRNAs of relevant proteins to regulate the process of viral infections. As identified for cytokines, the miR-548 family (including miR548b-5p, miR-548c-5p, miR-548i, miR-548j, and miR-548n) targeted the 3′ UTR of IFN-λ1, resulting in suppression of EV71 infection.…”

Section: Mirnas Machinery Regulate the Picornavirusmentioning

confidence: 99%

Cellular microRNAs and Picornaviral Infections

et al. 2014

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MiR-342-5p suppresses coxsackievirus B3 biosynthesis by targeting the 2C-coding region

Cited by 68 publications

References 51 publications

Human MicroRNA hsa-miR-296-5p Suppresses Enterovirus 71 Replication by Targeting the Viral Genome

Human MicroRNA hsa-miR-296-5p Suppresses Enterovirus 71 Replication by Targeting the Viral Genome

Coxsackievirus B3 Engineered To Contain MicroRNA Targets for Muscle-Specific MicroRNAs Displays Attenuated Cardiotropic Virulence in Mice

Cellular microRNAs and Picornaviral Infections

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