• RNA virus
• immunity modulation
• miR‐155
• viral genes

• MicroRNAs/genetics
• MicroRNAs/metabolism
• Animals
• Virus Replication
• Fish Diseases/immunology
• Fish Diseases/virology
• Infectious hematopoietic necrosis virus/physiology
• Infectious pancreatic necrosis virus/physiology
• Rhabdoviridae Infections/veterinary
• Rhabdoviridae Infections/immunology
• Rhabdoviridae Infections/virology
• Cell Line
• Birnaviridae Infections/veterinary
• Birnaviridae Infections/immunology
• Birnaviridae Infections/virology
• Cyprinidae
• Interferons/metabolism
• Interferons/genetics

• National Research Foundation of Korea
• NRF-2022R1I1A2068984 Ministry of Education
• RS-2023-00238630 Ministry of Education

• cross-kingdom regulation
• delivery strategies
• macrophage
• pharmacological activities
• plant derived nucleic acids

• Animals
• Exosomes/metabolism
• MicroRNAs/metabolism
• Neoplasms/drug therapy
• Neoplasms/genetics
• Nucleic Acids/therapeutic use
• Plants/genetics

• Enterovirus 71
• Foot and mouth disease
• Hand
• Viral replication
• Wnt signaling pathway
• miR-342-5p

• Animals
• Mice
• Enterovirus
• Enterovirus A, Human/genetics
• Interleukin-10
• Interleukin-6
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Tumor Necrosis Factor-alpha

• Antiviral
• Viral hemorrhagic septicemia virus
• miR-155
• microRNAs

• Animals
• Antiviral Agents
• Cell Line, Tumor
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Novirhabdovirus/physiology
• Carcinoma
• Hemorrhagic Septicemia, Viral
• Fish Diseases
• Mammals/metabolism

Coxsackievirus B (CVB), a member of Enterovirus genus of Picornaviridae, is the leading pathogen of viral myocarditis and dilated cardiomyopathy. The pathogenesis of CVB-induced myocarditis has not been completely elucidated, and no specific antiviral measurement is available presently. Circular RNAs (circRNAs) have been reported to be able to modulate viral replication and infection through bridging over non-coding RNAs (ncRNAs) and coding messenger RNAs (mRNAs). To date, the role of circRNAs in CVB infection is largely unknown. In this study, we found that hsa_circ_0076631 (circ_0076631) significantly promoted CVB type 3 (CVB3) replication. Further study showed that the underneath mechanism was circ_0076631 indirectly interacting with CVB3 through sponging miR-214-3p, which targeted the 3D-coding region of CVB3 genome to suppress viral translation. Knocking down circ-0076631 caused a suppression of CVB3 infection; thus, circ-0076631 may be a potential target for anti-CVB therapy.

• Madin–Darby canine kidney
• Seasonal influenza viruses
• enhancing the yield
• microRNA

Noncoding RNAs (ncRNAs) represent the largest and main transcriptome products and play various roles in the biological activity of cells and pathological processes. Accumulating evidence shows that microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA) are important ncRNAs that play vital regulatory roles during viral infection. Hand-foot-mouth disease (HFMD) virus causes hand-foot-mouth disease, and is also associated with various serious complications and high mortality. However, there is currently no effective treatment. In this review, we focus on advances in the understanding of the modulatory role of ncRNAs during HFMD virus infection. Specifically, we discuss the generation, classification, and regulatory mechanisms of miRNA, lncRNA, and circRNA in the interaction between virus and host, with a particular focus on their influence with viral replication and infection. Analysis of these underlying mechanisms can help provide a foundation for the development of ncRNA-based antiviral therapies.

• COVID-19
• microRNA
• respiratory viruses

• Enterovirus A71
• Picornaviridae
• antiviral agent
• biochemistry
• foot and mouth disease
• genetics
• hand
• microbiology
• molecular biology
• molecular epidemiology
• vaccine
• virology

Enterovirus 71 (EV71) is the main pathogenic virus that causes hand, foot, and mouth disease (HFMD). Studies have reported that EV71-induced infections including aseptic meningitis, acute flaccid paralysis, and even neurogenic pulmonary edema, can progress to severe neurological complications in infants, young children, and the immunosuppressed population. However, the mechanisms through which EV71 causes neurological diseases have not been fully explored. Non-coding RNAs (ncRNAs), are RNAs that do not code for proteins, play a key role in biological processes and disease development associated with EV71. In this review, we summarized recent advances concerning the impacts of ncRNAs on neurological diseases caused by interaction between EV71 and host, revealing the potential role of ncRNAs in pathogenesis, diagnosis and treatment of EV71-induced neurological complications.

• Child
• Child, Preschool
• Enterovirus
• Enterovirus A, Human/genetics
• Enterovirus Infections/complications
• Hand, Foot and Mouth Disease/complications
• Humans
• Infant
• RNA, Untranslated/genetics

• National Natural Science Foundation of China
• Key Technologies Research and Development Program of Anhui Province

The ongoing pandemic that resulted from coronavirus disease (COVID-19), which is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), had been spiraling out of control with no known antiviral drugs or vaccines. Due to the extremely serious nature of the disease, it has claimed many lives, with a mortality rate of 3.4% declared by the World Health Organization (WHO) on March 3, 2020. The aim of this study is to gain an understanding of the regulatory nature of the proteins involved in COVID-19 and to explore the possibility that microRNA (miRNA) could become a major component in the decoding of the virus. In the study, we were able to correlate the host protein gene BCL2L1 with miRNA miR-23b via network analysis. MiRNAs have previously been associated with the antiviral properties of various viral diseases, such as enterovirus 71 and hepatitis. They have been reported to act as antiviral regulators, since they are an integral component in the direct regulation of viral genes. MiRNAs are also capable of enabling the virus to avoid the host immune response by suppressing the IFN-α/β signaling pathway or increasing the production of IFN-α/β and as a result, inhibiting the viral infection. Here, we explain and shed light on the various correlations in the miRNA-gene-disease association that are seen in the host proteins of COVID-19.

• Enterovirus 71
• MiRNAs
• RD cell
• VP3
• Virus replication

MicroRNAs (miRNAs) belong to a class of non-coding RNAs that suppress gene expression by complementary oligonucleotide binding to the sites in target messenger RNAs. Numerous studies have demonstrated that miRNAs play crucial role in virtually all cellular processes of both plants and animals, such as cell growth, cell division, differentiation, proliferation and apoptosis. The study of rice MIR168a has demonstrated for the first time that exogenous plant MIR168a influences cholesterol transport in mice by inhibiting low-density lipoprotein receptor adapter protein 1 expression. Inspired by this finding, the cross-kingdom regulation of plant-derived miRNAs has drawn a lot of attention because of its capability to provide novel therapeutic agents in the treatment of miRNA deregulation-related diseases. Notably, unlike mRNA, some plant miRNAs are robust because of their 3′ end modification, high G, C content, and the protection by microvesicles, miRNAs protein cofactors or plant ingredients. The stability of these small molecules guarantees the reliability of plant miRNAs in clinical application. Although the function of endogenous miRNAs has been widely investigated, the cross-kingdom regulation of plant-derived miRNAs is still in its infancy. Herein, this review summarizes the current knowledge regarding the anti-virus, anti-tumor, anti-inflammatory, anti-apoptosis, immune modulation, and intestinal function regulation effects of plant-derived miRNAs in mammals. It is expected that exploring the versatile role of plant-derived miRNAs may lay the foundation for further study and application of these newly recognized, non-toxic, and inexpensive plant active ingredients.

• activity
• cross-kingdom regulation
• gene expression
• microRNA
• plant

As the causative agent of Newcastle disease (ND), Newcastle disease virus (NDV) has seriously restricted the development of the poultry industry. Previous research has shown that miRNAs, members of the small noncoding RNA family, are implicated in the regulation NDV replication through extensive interactions with host mRNAs, but whether miRNAs affect NDV replication by directly binding to the NDV antigenome remains unclear. In this study, potential Gallus gallus miRNAs targeting the antigenome of NDV were bioinformatically predicted using the online software RegRNA 2.0, and gga-miR-1603 and gga-miR-1794 were identified as targeting the viral L gene directly through dual-luciferase reporter assays. Sequence alignment analysis demonstrated that multiple genotypes of NDVs harbored highly conserved binding sites for gga-miR-1603 and gga-miR-1794 in the viral antigenome located at 8611–8634 nt and 14,490–14,514 nt, respectively. Meanwhile, we found that gga-miR-1603 and gga-miR-1794 negatively regulated the expression of viral L gene at both the RNA and protein levels, as well as viral replication in vitro. Furthermore, NDV infection had no effect on endogenous gga-miR-1603 and gga-miR-1794 expression in various avian cell lines. Overall, our present study demonstrated that gga-miR-1603 and gga-miR-1794 directly bind to the viral L gene to facilitate ts degradation and inhibit the replication of multiple genotypes of NDVs in vitro. These findings will provide us with important clues for antiviral therapy against NDV infection.

• Newcastle disease virus
• gga-miR-1603
• gga-miR-1794
• l gene
• miRNAs

Foot-and-mouth disease (FMD) endangers a large number of livestock populations across the globe being a highly contagious viral infection in wild and domestic cloven-hoofed animals. It adversely affects the socioeconomic status of millions of households. Vaccination has been used to protect animals against FMD virus (FMDV) to some extent but the effectiveness of available vaccines has been decreased due to high genetic variability in the FMDV genome. Another key aspect that the current vaccines are not favored is they do not provide the ability to differentiate between infected and vaccinated animals. Thus, RNA interference (RNAi) being a potential strategy to control virus replication, has opened up a new avenue for controlling the viral transmission. Hence, an attempt has been made here to establish the role of RNAi in therapeutic developments for FMD by computationally identifying (i) microRNA (miRNA) targets in FMDV using target prediction algorithms, (ii) targetable genomic regions in FMDV based on their dissimilarity with the host genome and, (iii) plausible anti-FMDV miRNA-like simulated nucleotide sequences (SNSs). The results revealed 12 mature host miRNAs that have 284 targets in 98 distinct FMDV genomic sequences. Wet-lab validation for anti-FMDV properties of 8 host miRNAs was carried out and all were observed to confer variable magnitude of antiviral effect. In addition, 14 miRBase miRNAs were found with better target accessibility in FMDV than that of Bostaurus. Further, 8 putative targetable regions having sense strand properties of siRNAs were identified on FMDV genes that are highly dissimilar with the host genome. A total of 16 SNSs having > 90% identity with mature miRNAs were also identified that have targets in FMDV genes. The information generated from this study is populated at http://bioinformatics.iasri.res.in/fmdisc/ to cater the needs of biologists, veterinarians and animal scientists working on FMD.

• Enterovirus A71
• NLRX1
• Pyroptosis
• miR-195

• ACE2
• COVID-19
• SARS-CoV-2
• TMPRSS2
• microRNA

• Angiotensin-Converting Enzyme 2/genetics
• Angiotensin-Converting Enzyme 2/metabolism
• Computational Biology/methods
• Gene Silencing
• Genome, Viral
• Humans
• Interferons/genetics
• Interferons/metabolism
• MicroRNAs/chemistry
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA, Messenger/chemistry
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• SARS-CoV-2/genetics
• Serine Endopeptidases/genetics
• Serine Endopeptidases/metabolism
• Transcriptome
• Viral Proteins/genetics

• HL115141 NIH HHS
• HL134849 NIH HHS
• HL148207 NIH HHS
• HL153356 NIH HHS
• HL148355 NIH HHS
• 18SFRN33900144 American Heart Association
• 20SFRN35200163 American Heart Association

• Enterovirus 71
• FOXO3/IRF7 pathway
• miR-155-5p

Enterovirus A71 (EV-A71) causes hand, foot, and mouth disease (HFMD) that is associated with neurological complications. Researchers have shown that exosomes containing host cellular microRNA (miRNA) can modulate the recipient's cellular response during viral infection. However, it is unclear how exosomal miRNAs regulate this response during EV-A71 infection. In this study, we used an exosomal miRNA chip to show that microRNA-155 (miR-155) was markedly enriched in exosomes after EV-A71 infection. Moreover, exosomal miR-155 efficaciously inhibited EV-A71 infection by targeting phosphatidylinositol clathrin assembly protein (PICALM) in recipient cells. Importantly, we confirmed that exosomal miR-155 reduced EV-A71 infection severity in vivo. Additionally, miR-155 levels in throat swabs from EV-A71-infected patients were higher than in those from healthy individuals. Collectively, our findings provide evidence that exosomal miR-155 plays a role in host-pathogen interactions by mediating EV-A71 infection via the repression of PICALM; these results provide insights into the regulatory mechanisms of viral infection.

• Enterovirus A71
• Exosomes
• MicroRNA-155
• PICALM

Eastern equine encephalitis virus (EEEV), a mosquito-borne RNA virus, is one of the most acutely virulent viruses endemic to the Americas, causing between 30% and 70% mortality in symptomatic human cases. A major factor in the virulence of EEEV is the presence of four binding sites for the hematopoietic cell-specific microRNA, miR-142-3p, in the 3’ untranslated region (3’ UTR) of the virus. Three of the sites are “canonical” with all 7 seed sequence residues complimentary to miR-142-3p while one is “non-canonical” and has a seed sequence mismatch. Interaction of the EEEV genome with miR-142-3p limits virus replication in myeloid cells and suppresses the systemic innate immune response, greatly exacerbating EEEV neurovirulence. The presence of the miRNA binding sequences is also required for efficient EEEV replication in mosquitoes and, therefore, essential for transmission of the virus. In the current studies, we have examined the role of each binding site by point mutagenesis of the seed sequences in all combinations of sites followed by infection of mammalian myeloid cells, mosquito cells and mice. The resulting data indicate that both canonical and non-canonical sites contribute to cell infection and animal virulence, however, surprisingly, all sites are rapidly deleted from EEEV genomes shortly after infection of myeloid cells or mice. Finally, we show that the virulence of a related encephalitis virus, western equine encephalitis virus, is also dependent upon miR-142-3p binding sites.

Eastern equine encephalitis virus (EEEV) is one of the most acutely virulent mosquito-borne viruses in the Americas. A major determinant of EEEV virulence is a mammalian microRNA (miRNA) that is primarily expressed in hematopoietic cells, miR-142-3p. Like miRNA suppression of host mRNA, miR-142-3p binds to the 3’ untranslated region (UTR) of the EEEV genome only in myeloid cells suppressing virus replication and the induction of the innate immune response. In this study, we used point mutations in all four miR-142-3p binding sites in the EEEV 3’ UTR to understand the mechanism behind this miRNA suppression. We observed that decreasing the number of miR-142-3p binding sites leads to virus escape and ultimately attenuation in vivo. Furthermore, another virus, western equine encephalitis virus, also encodes miR-142-3p binding sites that contribute to virulence in vivo. These results provide insight into the mechanism of how cell-specific miRNAs can mediate suppression of virus replication.

• 3' Untranslated Regions/genetics
• Aedes
• Animals
• Binding Sites/genetics
• Cell Line
• Cricetinae
• Encephalitis Virus, Eastern Equine/genetics
• Encephalitis Virus, Eastern Equine/immunology
• Encephalitis Virus, Eastern Equine/pathogenicity
• Encephalitis Virus, Western Equine/genetics
• Encephalitis Virus, Western Equine/immunology
• Encephalitis Virus, Western Equine/pathogenicity
• Encephalomyelitis, Equine/immunology
• Encephalomyelitis, Equine/virology
• Female
• Immunity, Innate/immunology
• L Cells
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• MicroRNAs/genetics
• RAW 264.7 Cells
• Virulence/genetics
• Virus Replication/genetics

• R01 AI095436 NIAID NIH HHS
• R21 AI111115 NIAID NIH HHS
• R21 AI132909 NIAID NIH HHS
• National Institute of Allergy and Infectious Diseases
• Defense Threat Reduction Agency

Enterovirus A71 (EV-A71) is an important emerging virus posing a threat to children under five years old. EV-A71 infection in infants or young children can cause hand-foot-and-mouth disease, herpangina, or severe neurological complications. However, there are still no effective antivirals for treatment of these infections. In this review, we summarize the antiviral compounds developed to date based on various targets of the EV-A71 life cycle. Moreover, development of a vaccine would be the most effective approach to prevent EV-A71 infection. Therefore, we also summarize the development and clinical progress of various candidate EV-A71 vaccines, including inactivated whole virus, recombinant VP1 protein, synthetic peptides, viral-like particles, and live attenuated vaccines.

• Antivirals
• Enterovirus A71
• Vaccines

Although the role of exogenous small interfering RNA (siRNA) and P-element induced wimpy testis (PIWI)-interacting RNA (piRNA) pathways in mosquito antiviral immunity is increasingly better understood, there is still little knowledge regarding the role of mosquito cellular microRNA (miRNA). Identifying direct interactions between the mosquito miRNAs and the RNA genome of arboviruses and choosing the relevant miRNA candidates to explore resulting antiviral mechanisms are critical. Here, we carried out genomic analyses to identify Aedes aegypti miRNAs that potentially interact with various lineages and genotypes of chikungunya, dengue, and Zika viruses. By using prediction tools with distinct algorithms, several miRNA binding sites were commonly found within different genotypes/and or lineages of each arbovirus. We further analyzed those miRNAs that could target more than one arbovirus, required a low energy threshold to form miRNA-viralRNA (vRNA) complexes, and predicted potential RNA structures using RNAhybrid software. We predicted miRNA candidates that might participate in regulating arboviral replication in Ae. aegypti. Even without any experimental validation, which should be done as a next step, this study can shed further light on the role of miRNA in mosquito innate immunity and targets for future studies.

• Aedes aegypti
• Zika
• arboviruses
• chikungunya
• dengue
• miRNA

• Coxsackievirus A16 (CA16)
• Enterovirus 71 (EV71)
• Hand, foot and mouth disease (HFMD)
• High-throughput sequencing
• microRNAs (miRNAs)

• Cells, Cultured
• Computational Biology
• Coxsackievirus Infections/genetics
• Coxsackievirus Infections/virology
• Enterovirus/pathogenicity
• Enterovirus A, Human/pathogenicity
• Enterovirus Infections/genetics
• Enterovirus Infections/virology
• Gene Expression Profiling/methods
• Gene Ontology
• Gene Regulatory Networks/genetics
• Hand, Foot and Mouth Disease/genetics
• Hand, Foot and Mouth Disease/virology
• High-Throughput Nucleotide Sequencing/methods
• Host-Pathogen Interactions/genetics
• Human Umbilical Vein Endothelial Cells
• Humans
• MicroRNAs/genetics

• DNMT3B
• enterovirus 71
• hsa-miR-17∼92
• methylation
• promoter

• AQP5
• Apoptosis
• Hepatitis B virus
• Hepatocellular carcinoma
• Proliferation
• miR-325-3p

• Apoptosis
• Aquaporin 5/genetics
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/physiopathology
• Cell Line, Tumor
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Hep G2 Cells
• Hepatitis B/complications
• Humans
• Liver Neoplasms/etiology
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/physiopathology
• MicroRNAs/metabolism
• MicroRNAs/physiology

• Enterovirus 71 (EV71)
• Functional genomics
• Nonstructural protein
• Structural protein
• Viral protein function

• Coxsackievirus A16
• Enterovirus 71
• Hand, foot, and mouth disease
• High-throughput sequencing
• Peripheral blood mononuclear cells
• microRNAs

• SILAC
• TargetScan
• enterovirus A71
• miR-197
• microRNA
• viral replication

Enterovirus 71 (EV71) is the main pathogen of severe hand-foot-mouth disease (HFMD). Long non-coding RNAs (lncRNAs) are recognized as pivotal factors during the pathogenesis of viral infection. However, the critical functions of lncRNAs in EV71–host interactions have not been characterized. Here, for the first time, we performed global transcriptome analysis of lncRNA and mRNA expression profiles in EV71-infected human rhabdomyosarcoma (RD) cells and skeletal muscle of mice using second-generation sequencing. In our study, a total of 3801 novel lncRNAs were identified. In addition, 23 lncRNAs and 372 mRNAs exhibited remarkable differences in expression levels between infected and uninfected RD cells, while 104 lncRNAs and 2647 mRNAs were differentially expressed in infected skeletal muscle from neonatal mice. Comprehensive bioinformatics analysis included target gene prediction, lncRNA-mRNA co-expression network construction, as well as gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis mainly focused on differentially-expressed genes (DEGs). Our results suggest that lncRNAs may participate in EV71 infection-induced pathogenesis through regulating immune responses, protein binding, cellular component biogenesis and metabolism. The present study provides novel insights into the functions of lncRNAs and the possible pathogenic mechanism following EV71 infection.

• Enterovirus 71
• RD cells
• RNA sequencing
• hand-foot-mouth disease
• long non-coding RNA
• skeletal muscle

• EV71
• PI3K/AKT
• apoptosis
• hsa-miR-494-3p
• viral replication

• EV71
• NFκB
• inflammation
• innate immunity
• miR‐9

• MicroRNA
• acute infection
• coxsackievirus
• enterovirus
• persistent infection

Enterovirus 71 (EV71) is the predominant causative pathogen of hand-foot-and-mouth disease (HFMD). Contrary to other HFMD-causing enterovirus, EV71 can lead to severe neurological complications, even death. MicroRNAs (miRNAs) are small non-coding RNAs that constitute the largest family of gene regulators participating in numerous biological or pathological processes. We previously reported that miR-16-5p increases with severity of HFMD by investigating the expression patterns of host miRNAs in patients with HFMD. However, the mechanisms by which EV71 induces miR-16-5p expression are not clear, and the interaction between EV71 and miR-16-5p is not yet fully understood. Here, we confirmed EV71-induced expression of miR-16-5p both in vitro and in vivo and show that upregulation of miR-16-5p by EV71 infection may occur at the posttranscriptional level. Moreover, EV71-induced caspase activation facilitates the processing of pri-miR-16-1. We also revealed that miR-16-5p can promote EV71-induced nerve cells apoptosis through activating caspase-3. In addition, we found that miR-16-5p can inhibit EV71 replication. CCNE1 and CCND1, two important cell cycle regulators, play an important role in the suppression of EV71 replication by miR-16-5p. Therefore, miR-16-5p is a positive feedback regulator in EV71-induced apoptosis and a suppressor of virus replication. These results help in understanding the interaction network between miRNA and EV71 infection and provide a potential target for the development of antiviral therapy.

• Enterovirus 71
• IL-6R
• STAT3
• miRNA-124

• Cancer
• Non-coding RNA
• Transcriptional control
• Tumor

• Cardiovascular Diseases/genetics
• Cell Differentiation
• Cell Lineage
• Epigenesis, Genetic
• Feedback, Physiological
• Gene Expression Regulation
• Genetic Predisposition to Disease
• Humans
• MicroRNAs/genetics
• Neoplasms/genetics
• Regenerative Medicine
• Virus Diseases/genetics

• Gene expression
• Latency
• Latent infection
• Persistence
• miRNA

• Cell Line
• Coxsackievirus Infections/complications
• Coxsackievirus Infections/genetics
• Coxsackievirus Infections/virology
• Diabetes Mellitus, Type 1/etiology
• Diabetes Mellitus, Type 1/genetics
• Diabetes Mellitus, Type 1/virology
• Enterovirus B, Human/physiology
• Gene Expression Regulation
• Humans
• MicroRNAs/genetics
• Pancreas/cytology
• Pancreas/metabolism
• Pancreas/virology

• NA Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche, Université Lille 2 (Equipe d'accueil 3610)
• NA Centre Hospitalier Régional et Universitaire de Lille
• GA-261441-PEVNET EU FP7
• Ministère de l’Education Nationale, de l’Enseignement Supérieur et de la Recherche, Université Lille 2 (Equipe d’accueil 3610)

Enterovirus 71 (EV71) is the major causative agent of hand‐foot‐and‐mouth disease in young children and can cause severe cerebral and pulmonary complications and even fatality. This study aimed at elucidating whether and how EV71 infection is regulated by a cellular microRNA, miR‐127‐5p. We found that miR‐127‐5p can downregulate the expression of SCARB2, a main receptor of EV71, by targeting two potential sites in its 3′ UTR region and inhibit EV71 infection. Meanwhile, miR‐127‐5p expression was upregulated during EV71 infection. Notably, transfecting cells with miR‐127‐5p mimics led to a significant decrease in viral replication, while inhibition of endogenous miR‐127‐5p facilitated viral replication. Furthermore, our evidence showed that miR‐127‐5p did not affect postentry viral replication. Taken together, these results indicated that miR‐127‐5p inhibited EV71 replication by targeting the SCARB2 mRNA.

• Enterovirus 71
• SCARB2
• miR‐127‐5p
• viral replication

• CAR
• Coxsackievirus B4
• PDX-1
• miRNA
• pancreatic cells
• persistence

Human enterovirus 71 (EV71) causes severe hand, foot and mouse disease, accompanied by neurological complications. During the interaction between EV71 and the host, the virus subverts host cell machinery for its own replication. However, the roles of microRNAs (miRNAs) in this process remain obscure.

In this study, we found that the miRNA hsa-let-7c-5p was significantly upregulated in EV71-infected rhabdomyosarcoma cells. The overexpression of hsa-let-7c-5p promoted replication of the virus, and the hsa-let-7c-5p inhibitor suppressed viral replication. Furthermore, hsa-let-7c-5p targeted mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and inhibited its expression. Interestingly, downregulation of MAP4K4 expression led to an increase in EV71 replication. In addition, MAP4K4 knockdown or transfection with the hsa-let-7c-5p mimic led to activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway, whereas the hsa-let-7c-5p inhibitor inhibited activation of this pathway. Moreover, EV71 infection promoted JNK pathway activation to facilitate viral replication.

Our data suggested that hsa-let-7c-5p facilitated EV71 replication by inhibiting MAP4K4 expression, which might be related to subversion of the JNK pathway by the virus. These results may shed light on a novel mechanism underlying the defense of EV71 against cellular responses. In addition, these findings may facilitate the development of new antiviral strategies for use in future therapies.

The online version of this article (doi:10.1186/s13578-017-0135-9) contains supplementary material, which is available to authorized users.

• EV71
• Hsa-let-7c-5p
• JNK
• MAP4K4

microRNAs (miRNAs) are non-coding RNAs that regulate many processes within a cell by manipulating protein levels through direct binding to mRNA and influencing translation efficiency, or mRNA abundance. Recent evidence demonstrates that miRNAs can also affect RNA virus replication and pathogenesis through direct binding to the RNA virus genome or through virus-mediated changes in the host transcriptome. Here, we review the current knowledge on the interaction between RNA viruses and cellular miRNAs. We also discuss how cell and tissue-specific expression of miRNAs can directly affect viral pathogenesis. Understanding the role of cellular miRNAs during viral infection may lead to the identification of novel mechanisms to block RNA virus replication or cell-specific regulation of viral vector targeting.

Some RNA viruses possess miRNA-binding sites in a range of locations within the viral genome, including the 5′ and 3′ non-translated regions.

Host cell miRNAs can bind to RNA virus genomes, enhancing genome stability, repressing translation of the viral genome, or altering free miRNA levels within the cell.

miRNAs contribute to viral pathogenesis by promoting evasion of the host antiviral immune response, enhancing viral replication, or, potentially, altering miRNA-mediated host gene regulation.

RNA virus infection can lead to widespread changes in the host transcriptome by modulating cell-specific miRNA levels.

• RNA viruses
• innate immunity
• miRNA
• pathogenesis

• Enterovirus
• Immunology
• MicroRNAs
• Type 1 diabetes
• Virology
• β cell

• Animals
• Autoimmune Diseases/etiology
• Diabetes Mellitus, Type 1/etiology
• Diabetes Mellitus, Type 1/therapy
• Enterovirus Infections/complications
• Gene Expression Regulation
• Humans
• Immune System/physiology
• Insulin-Secreting Cells/physiology
• MicroRNAs/physiology
• Neoplasms/etiology
• Virus Replication

• cytomegalovirus
• micro-RNA

There are no currently available specific antiviral therapies for non-polio Enterovirus infections. Although several vaccines have entered clinical trials, the efficacy requires further evaluation, particularly for cross-strain protective activity. Curing patients with viral infections is a public health problem due to antigen alterations and drug resistance caused by the high genomic mutation rate. To conquer these limits in the development of anti-Enterovirus treatments, a comprehensive understanding of the interactions between Enterovirus and host cells is urgently needed. MicroRNA (miRNA) constitutes the biggest family of gene regulators in mammalian cells and regulates almost a half of all human genes. The roles of miRNAs in Enterovirus pathogenesis have recently begun to be noted. In this review, we shed light on recent advances in the understanding of Enterovirus infection-modulated miRNAs. The impacts of altered host miRNAs on cellular processes, including immune escape, apoptosis, signal transduction, shutdown of host protein synthesis and viral replication, are discussed. Finally, miRNA-based medication provides a promising strategy for the development of antiviral therapy.

• apoptosis
• microRNA
• non-coding RNA
• protein synthesis shutdown
• virus replication

• Animals
• Enterovirus/genetics
• Enterovirus/pathogenicity
• Enterovirus/physiology
• Enterovirus Infections/genetics
• Enterovirus Infections/metabolism
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Virulence

The genus Enterovirus, a member of the Picornavirus family, are RNA viruses that can cause poliomyelitis, hand-food-mouth disease, viral meningitis or meningoencephalitis, viral myocarditis and so on. MicroRNAs are a class of highly conserved, small noncoding RNAs recognized as important regulators of gene expression. Recent studies found that MicroRNAs play a significant role in the infection of Enterovirus, such as enterovirus 71, coxsackievirus B3 and other Enterovirus. Enteroviral infection can alter the expression of cellular MicroRNAs, and cellular MicroRNAs can modulate viral pathogenesis and replication by regulating the expression level of viral or host's genes. Herein, this review summarizes the role of MicroRNAs in enteroviral infection.

• Enterovirus
• Infection
• MicroRNAs

Human enterovirus 71 (HEV71) is the cause of hand, foot and mouth disease and associated neurological complications in children under five years of age. There has been an increase in HEV71 epidemic activity throughout the Asia-Pacific region in the past decade, and it is predicted to replace poliovirus as the extant neurotropic enterovirus of highest global public health significance. To date there is no effective antiviral treatment and no vaccine is available to prevent HEV71 infection. The increase in prevalence, virulence and geographic spread of HEV71 infection over the past decade provides increasing incentive for the development of new therapeutic and prevention strategies against this emerging viral infection. The current review focuses on the potential, advantages and disadvantages of these strategies. Since the explosion of outbreaks leading to large epidemics in China, research in natural therapeutic products has identified several groups of compounds with anti-HEV71 activities. Concurrently, the search for effective synthetic antivirals has produced promising results. Other therapeutic strategies including immunotherapy and the use of oligonucleotides have also been explored. A sound prevention strategy is crucial in order to control the spread of HEV71. To this end the ultimate goal is the rapid development, regulatory approval and widespread implementation of a safe and effective vaccine. The various forms of HEV71 vaccine designs are highlighted in this review. Given the rapid progress of research in this area, eradication of the virus is likely to be achieved.

• Human enterovirus 71
• Infection
• Therapy
• Prevention
• Drugs
• Vaccine

Enterovirus 71 (EV71) is one of the major etiological pathogens of hand, foot and mouth disease (HFMD) and can cause severe cerebral and pulmonary complications and even fatality. MicroRNAs (miRNAs), a class of small non-coding RNA molecules, play an important role in post-transcriptional regulation of gene expression and thereby influencing various physiological and pathological processes. Increasing evidence suggests that miRNAs act as key effector molecules in the complicated pathogen-host interactions. However, the roles of miRNAs in EV71 infection and pathogenesis are not well understood.

To identify special miRNAs involved in EV71 infection, a microarray assay was performed to study the expression pattern of miRNAs in EV71-infected human rhabdomyosarcoma cells (RD cells) and uninfected RD cells. We further predicted the putative target genes for the dysregulated miRNAs using the online bioinformatic algorithms (TargetScan, miRanda and PicTar) and carried out functional annotation including GO enrichment and KEGG pathway analysis for miRNA predicted targets. Then, the results of microarray were further confirmed by quantitative RT-PCR.

Totally, 45 differentially expressed miRNAs ware identified by microarray, among which 36 miRNAs were up-regulated and 9 were down-regulated. 7166 predicted target genes for the dysregulated miRNAs were revealed by using TargetScan in conjunction with miRanda and PicTar. The GO annotation suggested that predicted targets of miRNAs were enriched into the category of signal transduction, regulation of transcription, metabolic process, protein phosphorylation, apoptotic process and immune response. KEGG pathway analysis suggested that these predicted target genes were involved in many important pathways, mainly including endocytosis and focal adhesion, MAPK signaling pathway, hypertrophic cardiomyopathy, melanogenesis and ErbB signaling pathway. The expression levels of 8 most differentially up-regulated miRNAs and 3 most differentially down-regulated miRNAs were confirmed by qRT-PCR. The expressions of hsa-miR-4530, hsa-miR-4492, hsa-miR-6125, hsa-miR-494-3p, hsa-miR-638, hsa-miR-6743-5p, hsa-miR-4459 and hsa-miR-4443 detected by qRT-PCR were consistent with the microarray data.

These results might extend our understanding to the regulatory mechanism of miRNAs underlying the pathogenesis of EV71 infection, thus strengthening the preventative and therapeutic strategies of HFMD caused by EV71.