MiR-10a* up-regulates coxsackievirus B3 biosynthesis by targeting the 3D-coding sequence

Tong, Lei; Lin, Lexun; Wu, Shuo; Guo, Zhiwei; Wang, Tianying; Qin, Ying; Wang, Ruixue; Zhong, Xiaoyan; Wu, Xia; Wang, Yan; Luan, Tian; Wang, Qiang; Li, Yunxia; Chen, Xiaofeng; Zhang, Fengmin; Zhao, Wenran; Zhong, Zhaohua

doi:10.1093/nar/gkt058

Cited by 67 publications

(47 citation statements)

References 46 publications

(48 reference statements)

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“…5b). The expression pattern determined by miRNA sequencing was confirmed by taqman RT-qPCR for 2 miRNAs that were described in the literature to be related to enteroviral infection: miR-146a-5p (upregulated) and miR-23b (downregulated) [45][46][47][48] ( Fig. 5c-d).…”

Section: Pattern Of Cellular Mirnas In Ductal-like Cells Persistentlysupporting

confidence: 53%

Persistence of Coxsackievirus B4 in pancreatic ductal-like cells results in cellular and viral changes

et al. 2017

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Introduction: Although known as cytolytic viruses, group B coxackieviruses (CVB) are able to establish a persistent infection in vitro and in vivo. Viral persistence has been reported as a key mechanism in the pathogenesis of CVB-associated chronic diseases such as type 1 diabetes (T1D). The impact of CVB4 persistence on human pancreas ductal-like cells was investigated. Methods: A persistent CVB4 infection was established in ductal-like cells. PDX-1 expression, resistance to CVB4-induced lysis and CAR expression were evaluated. The profile of cellular microRNAs (miRNAs) was investigated through miRNA-sequencing. Viral phenotypic changes were examined, and genomic modifications were assessed by sequencing of the viral genome. Results: The CVB4 persistence in ductal-like cells was productive, with continuous release of infectious particles. Persistently infected cells displayed a resistance to CVB4-induced lysis upon superinfection and expression of PDX-1 and CAR was decreased. These changes were maintained even after virus clearance. The patterns of cellular miRNA expression in mock-infected and in CVB4-persistently infected ductal-like cells were clearly different. The persistent infection-derived virus (PIDV) was still able to induce cytopathic effect but its plaques were smaller than the parental virus. Several mutations appeared in various PIDV genome regions, but amino acid substitutions did not affect the predicted site of interaction with CAR. Conclusion: Cellular and viral changes occur during persistent infection of human pancreas ductal-like cells with CVB4. The persistence of cellular changes even after virus clearance supports the hypothesis of a long-lasting impact of persistent CVB infection on the cells.

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Section: Pattern Of Cellular Mirnas In Ductal-like Cells Persistentlysupporting

confidence: 53%

Persistence of Coxsackievirus B4 in pancreatic ductal-like cells results in cellular and viral changes

et al. 2017

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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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“…149 For example, it was shown that miR-10a* promotes CVB3 biosynthesis by targeting the 3-dimensional coding sequence of CVB3 genomic RNA. 150 Moreover, certain miRNAs were found to contribute to the development of viral myocarditis without evidence of altering viral replication dynamics. One example is miR-21, whose change in expression levels during CVB3 infection is controversial because some studies indicated its upregulation, 70,151 whereas others demonstrate downregulation.…”

Section: Virus-induced Direct Damagementioning

confidence: 99%

Myocarditis

Gabriel

Luo

Qiu

et al. 2016

Circulation Research

405

375

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MiR-10a* up-regulates coxsackievirus B3 biosynthesis by targeting the 3D-coding sequence

Cited by 67 publications

References 46 publications

Persistence of Coxsackievirus B4 in pancreatic ductal-like cells results in cellular and viral changes

Persistence of Coxsackievirus B4 in pancreatic ductal-like cells results in cellular and viral changes

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

Myocarditis

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