Po Tien

Wuhan University, Wu-han-shih, Hubei, China

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Publications (158)569.76 Total impact

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    Dataset: c4ra11087k

    Full-text · Dataset · Oct 2015
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    Tai An · Shu Li · Wei Pan · Po Tien · Bo Zhong · Hong-Bing Shu · Shuwen Wu
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    ABSTRACT: Author Summary In recent years, the mechanisms of innate antiviral immune responses mediated by pattern recognition receptors (PRRs) have been heavily investigated. All PRRs require the key molecule TANK-binding kinase 1 (TBK1) to activate the transcription factor IRF3, which leads to type I interferon induction and the cellular antiviral response. Here, we identified the dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (DYRK2) as a negative regulator of TBK1. DYRK2 inhibited the virus-triggered induction of type I interferon and promoted K48-linked ubiquitination and the degradation of TBK1 in a manner that depended on its kinase activity. We further found that DYRK2 phosphorylated Ser527 of TBK1, which is essential for the recruitment of NLRP4 and for the E3 ubiquitin ligase DTX4 to degrade TBK1. Our findings suggest that DYRK2 plays an important role in innate immune responses to viruses by modulating TBK1 activity and provide important insights into the intricate regulatory mechanisms of the innate immune response against viruses.
    Full-text · Article · Sep 2015 · PLoS Pathogens
  • Hua Zhang · Lei Song · Haolong Cong · Po Tien
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    ABSTRACT: Enterovirus 71 (EV71) recruits various cellular factors to assist in the replication and translation of its genome. Identification of the host factors involved in the EV71 life cycle not only will enable a better understanding of the infection mechanism but also has the potential to be of use in the development of antiviral therapeutics. In this study, we demonstrated that the cellular factor 68-kDa Src-associated protein in mitosis (Sam68) acts as an internal ribosome entry site (IRES) trans-acting factor (ITAF) that binds specifically to the EV71 5' untranslated region (5'UTR). Interaction sites in both the viral IRES (stem-loops IV and V) and the heterogeneous nuclear ribonucleoprotein K homology (KH) domain of Sam68 protein were further mapped using an electrophoretic mobility shift assay (EMSA) and biotin RNA pulldown assay. More importantly, dual-luciferase (firefly) reporter analysis suggested that overexpression of Sam68 positively regulated IRES-dependent translation of virus proteins. In contrast, both IRES activity and viral protein translation significantly decreased in Sam68 knockdown cells compared with the negative-control cells treated with short hairpin RNA (shRNA). However, downregulation of Sam68 did not have a significant inhibitory effect on the accumulation of the EV71 genome. Moreover, Sam68 was redistributed from the nucleus to the cytoplasm and interacts with cellular factors, such as poly(rC)-binding protein 2 (PCBP2) and poly(A)-binding protein (PABP), during EV71 infection. The cytoplasmic relocalization of Sam68 in EV71-infected cells may be involved in the enhancement of EV71 IRES-mediated translation. Since Sam68 is known to be a RNA-binding protein, these results provide direct evidence that Sam68 is a novel ITAF that interacts with EV71 IRES and positively regulates viral protein translation.
    No preview · Article · Jul 2015 · Journal of Virology
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    ABSTRACT: Importance: RNAi has been well known to play important antiviral roles from plants to invertebrates. However, recent studies provided strong supports that RNAi is also involved in antiviral response in mammalian cells. An important indication for RNAi-mediated antiviral activity in mammals is the fact that a number of mammalian viruses encode potent suppressor of RNA silencing (VSR). Our current results demonstrate that coronaviruses N protein could function as a VSR through its dsRNA binding activity. Mutational analysis of N protein allowed us to find out the critical residues for the VSR activity. Using the MHV-A59 as the coronavirus replication model, we showed that ectopic expression of SARS-CoV N protein could promote MHV replication in RNAi-active cells but did not in RNAi depleted cells. These results indicate that coronaviruses encode a VSR that functions in the replication cycle, and provide further evidences to support that RNAi-mediated antiviral response exists in mammalian cells.
    Full-text · Article · Jun 2015 · Journal of Virology
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    ABSTRACT: A series of novel human enterovirus 71 inhibitors, N-benzyl-N-phenylthiophene-2-carboxamide analogues were synthesized and their antiviral activities were evaluated in vitro. Most derivatives of this structure against EV71 with a low micromolar range in the RD (Rhabdomyosarcoma) cell lines. The most potent compound 5a, N-(4-bromobenzyl)-N-(4-fluorophenyl)thiophene-2- carboxamide, showed low micromolar activity against EV71 (EC50 = 1.42 μM) compared to the reference anti-EV71 drug Enviroxime (EC50 = 0.15 μM). Preliminary SAR studies revealed that thiophene-2-carboxamide core is crucial for maintaining antiviral activity, and N-substituent phenyl groups largely influenced anti-EV71 efficacy of this new class of potent antiviral agents.
    Full-text · Article · Jun 2015 · RSC Advances
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    ABSTRACT: Nowadays there is a growing interest in bio-scaffolded nanoarchitectures. Rapid progress in nanobiotechnology and molecular biology has allowed the engineering of inorganic-binding peptides termed as genetically engineered polypeptides for inorganics (GEPIs) into self-assembling biological structures to facilitate the design of novel biomedical or bioimaging devices. Here we introduce a novel nanocomposite comprising a self-assembled protein scaffold based on a recombinant tobacco mild green mosaic tobamovirus (TMGMV) coat protein (CP) and the photocatalytic TiO2 nanoparticles attached to it, which may provide a generic method for materials engineering. A template containing a modified TMGMV CP (mCP) gene, with the first six C-terminal amino acid residues deleted to accommodate more foreign peptides and expressing a site-directed mutation of A123C for bioconjugation utility, and two genetically engineered mutants, Escherichia coli-based P-mCP-Ti7 containing a C-terminal TiO2 GEPI sequence of seven peptides (Ti7) and Hi5 insect cells-derived E-CP-Ti7-His6 C-terminally fused with Ti7+His6 tag were created. Expression vectors and protocols for enriching of the two CP variants were established and the resultant proteins were identified by western blot analysis. Their RNA-free self-assembling structures were analyzed by transmission electron microscopy (TEM) and immuno-gold labeling TEM analysis. Adherence of nanoparticles to the P-mCP-Ti7 induced protein scaffold was visualized by TEM analysis. Also discussed is the Cysteine thiol reactivity in bioconjugation reactions with the maleimide-functionalized porphyrin photosensitizers which can function as clinical photodynamic therapy agents. This study introduced a novel approach to producing an assembly-competent recombinant TMGMV CP, examined its ability to serve as a novel platform for the multivalent display of surface ligands and demonstrated an alternative method for nanodevice synthesis for nanobiotechnological applications by combining GEPIs-mediated immobilization with the controllability of self-assembling recombinant TMGMV CP.
    No preview · Article · Feb 2015 · Journal of Materials Science Materials in Medicine
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    ABSTRACT: Herein, we report the discovery of halolactone derivatives as efficient non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the study of their structure-activity relationships (SARs). Among them, 5-exo lactone 3-(chloro(2-chlorophenyl)-methyl)isobenzofuran-1(3H)-one 13a, showed excellent potency against WT HIV-1 in the reverse transcriptase gene with low EC50 value of 0.45 µM. In most cases, the property and the position of the substituents had a definite effect on the activities of anti-HIV-1 activity. In contrast, the 6-endo lactones (isochroman-1-ones) had inferior inhibitory activities against HIV-1. This work offered a structurally simple scaffold (isobenzofuran-1(3H)-one) for the development of novel anti-HIV drugs.
    Full-text · Article · Dec 2014 · RSC Advances
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    ABSTRACT: Chronic hepatitis B virus (HBV) infection could cause severe liver disease including cirrhosis, hepatocellular carcinoma, and end-stage liver failure in HIV positive individuals. The available data from clinical studies suggest that HIV infection modulates HBV specific T cell response. However, the virological and molecular aspects of HBV-HIV co-infection are currently poorly understood due to the lack of appropriate model systems. In this study, the effect of HIV infection on the life cycle of HBV was explored using an in vitro model system. The present data show that the extracellular and intracellular hepatitis B surface antigen (HBsAg) and e antigen (HBeAg) decrease significantly in HepG2 cells co-transfected with HIV NL4-3 and pHBV1.3 as compared to those cells only transfected with pHBV1.3. Moreover, a significant decrease of HBV DNA and mRNA expression was also observed in the co-transfected cells. HIV Rev protein, an RNA-bound regulatory protein, could significantly decrease the expression levels of extracellular and intracellular HBsAg and HBeAg by mediating the expression of HBV mRNA in cells co-transfected with plasmids containing HIV-1 Rev and pHBV1.3. Further experiments demonstrate that HIV Rev could manipulate neither the promoters of HBV nor the nuclear export of HBV mRNA, thus we propose that HIV Rev might affect the degradation process of HBV mRNA. These results from the in vitro model system might provide clues to understand further the rapid progression of liver disease in HIV-HBV co-infected patients.
    No preview · Article · Dec 2014 · AIDS Research and Human Retroviruses
  • Wei Zhang · Lei Zhang · Yanlu Zan · Ning Du · Yang Yang · Po Tien
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    ABSTRACT: The interferon (IFN) immune system plays an essential role in protecting the host against most viral infections. In order to explore the interactions between the IFN pathway and Respiratory syncytial virus (RSV) infection, and to identify potential IFN-stimulated genes (ISGs) that may be involved in suppressing the replication of RSV, we utilized an IFN pathway-specific microarray to study the effects of RSV infection on the IFN pathway in HeLa cells. We showed that RSV infection enhanced the expression of a series of ISGs, including oligoadenylate synthetase 2 (OAS2), interferon-induced transmembrane protein 1 (IFITM1) and myxovirus-resistance 2 (Mx2). Our results also showed that the IFITM proteins potently inhibited RSV infection mainly by interfering with both virus entry and the subsequent replication steps, but not the attachment process. The anti-viral effect of IFITM3 protein was not affected by ubiquitination modification. Furthermore, knocking down the endogenous and IFN-induced expressions of IFITM1 and IFITM3 proteins facilitated RSV infection. Expression of the IFITM proteins was found to delay the phosphorylation of interferon regulatory factor-3 (IRF3) through interfering with the detection of viral RNA by the melanoma differentiation-associated gene 5 (MDA5) and the retinoic acid-inducible gene I (RIG-I). These results demonstrated that the restriction of RSV infection by the IFITM proteins was achieved through the inhibition of virus entry and replication, and they provide further insight for exploring the mechanism of IFITM proteins-mediated virus restriction.
    No preview · Article · Sep 2014 · Journal of General Virology
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    ABSTRACT: Series of non-nucleoside reverse transcriptase inhibitors derived from indole-based α-amino acids were designed and synthesized. Their inhibitory activities have been detected by a TZM-bl cell assay on HIV virus type HIV-1IIIB. The comprehensive understanding of the SAR was obtained by utilizing the variation of the substituents of the indole-based α-amino acids. From the screened compounds, the novel inhibitors 19 and 29 were identified to be highly potent candidates with EC50 value of 0.060 μM and 0.045 μM respectively (CC50 value of 109.545 μM, 49.295 μM and SI value of 1825.8, 1095.4). While, in most cases, that variation of substituents at different position had a significant effect on the potency of activities. The results also indicate that the indole-based α-amino acids as efficient NNRTIs displayed comparable anti-HIV-1 activities with the reference drug NVP. We hope the identification of these indole-based amino acids as efficient NNRTIs of RT could stimulate researchers to develop more diversified anti-HIV drugs.
    Full-text · Article · Aug 2014 · Organic & Biomolecular Chemistry
  • Xuwen Pan · Huiguo Ding · Xuyu Zhou · Po Tien
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    ABSTRACT: Cytotoxic T lymphocyte (CTL) epitopes in the HBV protein of hepatitis B virus (HBV) may play a key role in viral control and liver damage. The aim of this study was to identify and study the function of HLA-A∗33:03-restricted CTL epitopes in HBV protein of the HBV genotypes B and C, which are epidemic in China. Sixteen HBV peptides were predicated by computational analysis, and synthesized peptides were examined for their affinity to HLA-A∗33:03 using a stable cell line. After being analyzed by enzyme-linked immunospot and cytolytic activity assays, as well as the tetramers staining method using peripheral blood mononuclear cells isolated from HBV-infected patients, five peptides (Hbs245–253, HBs335–343, HBc119–127, HBc104–112, and HBp391–399) were chosen to further confirm their HLA_A∗33:03 restriction in transgenic mice.
    No preview · Article · Jun 2014 · Biochemical and Biophysical Research Communications
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    ABSTRACT: Biomolecule-nanoparticle hybrid bioconjugates based on bioscaffolds such as protein cages and virus capsules have been widely studied. Highly stable and durable biotemplates are a vital pillar in constructing bio-inorganic functional hybrid composites. Here, we introduce a highly heat-resistant coat protein (CP) of Sulfolobus tengchongensis spindle-shaped virus 1 (STSV1) isolated from the hyperthermophilic archaeon as a prospective biological matrix. Our experiments showed that STSV1 CP was successfully cloned and solubly expressed in the Escherichia coli Rosetta-(DE3) host strain. Protein expression was verified by SDS-PAGE and western blot analysis of the reference C-terminally six-histidine (His6) tagged STSV1 CP (HT-CP). Thermal stability experiments showed that the STSV1 coat protein remained fairly stable at 80 °C. The proteins can be purified facilely by heat treatment followed by size exclusion chromatography (SEC). Transmission electron microscopy (TEM) analysis of the purified STSV1 CP protein aggregates demonstrated that the protein could self-assemble into rotavirus-like nanostructures devoid of genetic materials under our experimental conditions. Similar results were obtained for the HT-CP purified by heat treatment followed by Ni-NTA and SEC, indicating that moderately engineered STSV1 CP can retain its self-assembly property. In addition, the STSV1 CP has a high binding affinity for TiO2 nanoparticles. This illustrates that the STSV1 CP can be used as a bioscaffold in nanobiotechnological applications.
    No preview · Article · Jun 2014 · Extremophiles
  • Zhuo Yang · Po Tien
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    ABSTRACT: Objective: MicroRNAs (miRNAs) play an important role in infection and replication of virus in host cells. In this study, we examined miRNAs' effects on the replication of Coxsackievirus A16 (CA16) in rhabdomyosarcoma cells. Methods: We constructed target gene of miRNAs screening system. We used 3'untranslated region (UTR) dual luciferase reporter analysis to identify putative miRNA targets in the CA16 virus genome. First, 12 segments of CA16 virus genome were inserted to the pMIR vector and the luciferase expression were assayed to identify the target gene of putative miRNA. The reporter gene expression of the cells transfected with the vector containing 5'-UTR was significantly downregulated. Then, using online analysis programs we screened the miRNAs that may target to 5'-UTR. Furthermore, Western blot and real-time PCR test were used to study the effect of miRNAs on viral replication. Results: The study showed that miR432 * could stimulate the replication of CA16 virus. On the contrary, miR432 * inhibitor could suppress CA16 virus replication. Conclusion: Cellular miRNAs could regulate the replication of CA16 virus in host cells. Our findings support the notion that the cellular miRNAs play an important role in the host and virus infection.
    No preview · Article · Jun 2014 · ACTA MICROBIOLOGICA SINICA
  • Zhuo Yang · Po Tien
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    ABSTRACT: MicroRNAs (miRNAs) play an important role in infection and replication of virus in host cells. To identify cellular miRNAs involved in the host response to enterovirus 71 (EV71) infection, we examined miRNAs effects on the replication of EV71 in rhabdomyosarcoma cells. We constructed target gene of miRNAs screening system. 3'untranslated region (UTR) dual luciferase reporter analysis was used to identify putative miRNA targets in the EV71 virus genome. First, 13 segments of EV71 virus genomes were inserted to the pMIR vector and the luciferase expression were assayed to identify the target gene of putative miRNA. The reporter gene expression of the cells transfected with the vector containing 5'-UTR was significantly downregulated. Then we screened the miRNAs that may target to 5'-UTR using online analysis programs. Furthermore, Western blotting and real-time PCR test were performed to investigate the effect of miRNAs on viral replication. The study showed that miR373 and miR542-5p could suppress the replication of EV71 virus through binding to the 5'-UTR gene. Cellular miRNAs could regulate the replication of EV71 virus in host cells, and our paper should report the role of miR373 and miR542-5p in this regulation for the first time. Our findings supported the notion that the cellular miRNAs might be essential in the host-pathogen interactions.
    No preview · Article · Jun 2014 · Sheng wu gong cheng xue bao = Chinese journal of biotechnology
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    Xuwen Pan · Huiguo Ding · Xuyu Zhou · Po Tien
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    ABSTRACT: The Silences of the Archives, the Reknown of the Story. The Martin Guerre affair has been told many times since Jean de Coras and Guillaume Lesueur published their stories in 1561. It is in many ways a perfect intrigue with uncanny resemblance, persuasive deception and a surprizing end when the two Martin stood face to face, memory to memory, before captivated judges and a guilty feeling Bertrande de Rols. The historian wanted to go beyond the known story in order to discover the world of the heroes. This research led to disappointments and surprizes as documents were discovered concerning the environment of Artigat’s inhabitants and bearing directly on the main characters thanks to notarial contracts. Along the way, study of the works of Coras and Lesueur took a new direction. Coming back to the affair a quarter century later did not result in finding new documents (some are perhaps still buried in Spanish archives), but by going back over her tracks, the historian could only be struck by the silences of the archives that refuse to reveal their secrets and, at the same time, by the possible openings they suggest, by the intuition that almost invisible threads link here and there characters and events.
    Preview · Article · May 2014 · Biochemical and Biophysical Research Communications
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    ABSTRACT: To find novel compounds against H5N1, three series of known or novel small molecular polyphenols were synthesized and tested in vitro for anti-H5N1 activity. In addition, the preliminary structure-antiviral activity relationships were elaborated. The results showed that some small molecular polyphenols had better anti-H5N1 activity, and could serve as novel virus entry inhibitors against H5N1, likely targeting to HA2 protein. Noticeably, compound 4a showed the strongest activity against H5N1 among these compounds, and the molecular modeling analysis also suggested that this compound might target to HA2 protein. Therefore, compound 4a is well qualified to serve as a lead compound or scaffold for the further development of H5N1 entry inhibitor.
    No preview · Article · Apr 2014 · Bioorganic & medicinal chemistry letters
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    Wei Zhang · Lei Zhang · Zhiyong Wu · Po Tien
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    ABSTRACT: Exposure of cells to type I interferon (IFN) induces an antiviral state that prevents viral infection, but viruses can utilize multiple tactics to antagonize the host immune system. Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) are two major pathogens that cause hand, foot, and mouth disease (HFMD), which is prevalent among children. We found that both EV71 and CA16 have different reactions to type I IFN pretreatment and induction patterns of type I IFN on Rhabdomyosarcoma (RD) cells. Further, a human-α and β IFN PCR array was employed to analyze the expressions of 84 genes related to the type I IFN pathway. We found significant up-regulation of multiple genes in the presence of type I IFN and differential regulation patterns during EV71 or CA16 infection in RD cells. For instance, EV71 infection repressed the JAK-STAT signaling pathway and interferon-stimulated gene (ISG) expression, whereas CA16 infection normally triggers the JAK-STAT pathway, leading to the expression of ISGs. Taken together, this study provides a comprehensive view of the differential impacts of EV71 and CA16 infection on 84 genes in the IFN pathway, shedding light on the different resistances of these viruses to type I IFN treatment and cytotoxic effects in RD cells.
    Preview · Article · Apr 2014 · Biochemical and Biophysical Research Communications
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    ABSTRACT: Biomolecule-mediated assembly of novel nanoconjugates has been subjected to numerous investigations nowadays, which provides a new insight into the material science and engineering. Via the molecular biology technology, the genetically engineered polypeptide for inorganics (GEPI) can be designed as a molecular binder into the bio-scaffold to assemble hybrid functional nanoarchitectures. In the present work, we constructed a multi-functional virus-like particle (VLP) scaffold based on the Tobacco mosaic virus (TMV) (wild-type strain U1) in a facile way. The S123C site-mutated coat protein (CP) of TMV recombinated with a Ti–GEPI and 6-histidine tag (His tag) was successfully cloned, expressed and purified. The as-produced r-CP products retained both binding affinity for inorganic nanoparticles and self-assembly capability. Analysis of r-CP self-assembly during condensation polymerization was conducted. The r-CP-assembled aggregates including disc-like structures and rod-like VLPs were recovered by preparative size-exclusion chromatography (SEC) and then examined by TEM analysis. Notably, r-CP protein displayed a thermo-triggered reversibly switchable transition between bistable states of transparency and opaqueness. Western blot analysis, Immunogold labelling and TEM analysis were employed to test the existence and binding function of the His tag group in r-CP VLPs. Furthermore, dispersion of TiO2 NPs in r-CP solution and recyclable application in bio-benefication was introduced. Here we demonstrated the possibilities of combining peptide-mediated immobilization with VLP-based biotemplate bearing multi-binding moieties for prospectful functional applications.
    No preview · Article · Apr 2014 · Journal of Materials Science
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    ABSTRACT: Enterovirus 71 (EV71) is a highly transmissible pathogenic agent that causes severe central nervous system diseases in infected infants and young children. Here, we reported that EV71 VP1 protein could bind to vimentin intermediate filaments expressed on host cell surface. Soluble vimentin or an antibody against vimentin could inhibit the binding of EV71 to host cells. Accompanied with the reduction of vimentin expression on cell surface, the binding of EV71 to cells was remarkably decreased. Further evidence showed that the N terminal of vimentin is responsible for the interaction between EV71 and vimentin. These results indicated that vimentin on host cell surface may serve as an attachment site that mediated the initial binding and subsequently increased the infectivity of EV71. This study delivers important findings on the roles of vimentin filaments in relation to EV71 infection and provides information that not only improved our understanding of EV71 pathogenesis, but also presents us with potentially new strategies for the treatment of diseases caused by EV71 infections.
    Preview · Article · Mar 2014 · Journal of Virology
  • Wei Zhang · Lei Zhang · Zhiyong Wu · Po Tien
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    ABSTRACT: Exposure of cells to type I interferon (IFN) induces an antiviral state that prevents viral infection, but viruses can utilize multiple tactics to antagonize the host immune system. Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) are two major pathogens that cause hand, foot, and mouth disease (HFMD), which is prevalent among children. We found that both EV71 and CA16 have different reactions to type I IFN pretreatment and induction patterns of type I IFN on Rhabdomyosarcoma (RD) cells. Further, a human-α and β IFN PCR array was employed to analyze the expressions of 84 genes related to the type I IFN pathway. We found significant up-regulation of multiple genes in the presence of type I IFN and differential regulation patterns during EV71 or CA16 infection in RD cells. For instance, EV71 infection repressed the JAK-STAT signaling pathway and interferon-stimulated gene (ISG) expression, whereas CA16 infection normally triggers the JAK-STAT pathway, leading to the expression of ISGs. Taken together, this study provides a comprehensive view of the differential impacts of EV71 and CA16 infection on 84 genes in the IFN pathway, shedding light on the different resistances of these viruses to type I IFN treatment and cytotoxic effects in RD cells.
    No preview · Article · Jan 2014 · Biochemical and Biophysical Research Communications

Publication Stats

4k Citations
569.76 Total Impact Points

Institutions

  • 2003-2015
    • Wuhan University
      • • State Key Laboratory of Virology
      • • College of Life Sciences
      Wu-han-shih, Hubei, China
    • Government of the People's Republic of China
      Peping, Beijing, China
  • 1992-2015
    • Chinese Academy of Sciences
      • • Key Laboratory of Pathogenic Microbiology and Immunology
      • • Institute of Microbiology
      • • Department of Molecular Virology
      Peping, Beijing, China
  • 2011
    • Kunming Institute of Zoology CAS
      • State Key Laboratory of Genetic Resources and Evolution
      Yün-nan, Yunnan, China
  • 1993-2008
    • Academia Sinica
      • Institute of Plant and Microbial Biology
      T’ai-pei, Taipei, Taiwan
  • 2007
    • Case Western Reserve University
      • School of Medicine
      Cleveland, Ohio, United States
  • 2005
    • National Tsing Hua University
      Hsin-chu-hsien, Taiwan, Taiwan
    • Capital institute of Pediatrics
      Peping, Beijing, China
  • 2002
    • Oxford University Hospitals NHS Trust
      Oxford, England, United Kingdom
  • 2001-2002
    • National Space Science
      Peping, Beijing, China
  • 1982-2002
    • Beijing Institute of Microbiology and Epidemiology
      Peping, Beijing, China