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首页> 外文期刊>BMC Genomics >A computational tool for the design of live attenuated virus vaccine based on microRNA-mediated gene silencing
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A computational tool for the design of live attenuated virus vaccine based on microRNA-mediated gene silencing

机译：基于microRNA介导的基因沉默设计减毒活疫苗的计算工具

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Background The microRNA-based gene-silencing machinery has been recognized as a promising approach to control viral replication and used for improving safety for the live attenuated virus vaccines. The effective host microRNA response elements (MREs) have been incorporated into a virus sequence mainly based on the experimental trials for identifying both microRNA binding sites and effective mutations. The design of MREs for viral genomes or with multiple host microRNAs of interest, then, will be time and cost consuming. Results In this paper, we introduced a computational flow that could be used to design MREs of human microRNAs within Influenza A H1N1 virus gene segments. The main steps of the flow includes locating possible binding sites; MREs, of human microRNAs within the viral sequences using a miRNA target prediction tool (miranda), performing various mutations among mismatched binding positions, calculating the binding energy, score, identity, and the effects of changed physical properties of amino acids according to the changed bases in RNA level, and prioritizing the mutated binding sites. The top ranked MREs of human microRNA hsa-miR-93 is consistent with previous literature while other results waited to be experimentally verified. To make the computational flow easily accessible by virologists, we also developed MicroLive, a web server version of the MRE design flow together with the database of miranda-predicted MREs within gene sequences of seven RNA viruses including Influenza A, dengue, hepatitis C, measles, mumps, poliovirus, and rabies. Users may design MREs of specific human microRNAs for their input viral sequences using MRE design tool or optimize the miranda-predicted MREs of seven viruses available on the system. Also, users could design varied number of MREs for multiple human microRNAs to modulate the degree of live vaccine attenuation and reduce the likelihood of escape mutants. Conclusions The computational design of MREs helps reduce time and cost for experimental trials. While the flow was demonstrated using human microRNAs and Influenza A H1N1 virus, it could be flexibly applied to other hosts (e.g., animals) and viruses of interest for constructing host-specific live attenuated vaccines. Also, it could be deployed for engineering tissue-specific oncolytic viruses in cancer virotherapeutics. The MicroLive web server is freely accessible at http://www.biotec.or.th/isl/microlive.
机译：背景技术基于microRNA的基因沉默机制已被认为是控制病毒复制的一种有前途的方法，并用于提高减毒活疫苗的安全性。有效的宿主微RNA反应元件（MRE）已被纳入病毒序列，主要是基于用于鉴定微RNA结合位点和有效突变的实验研究。因此，针对病毒基因组或具有多个目标宿主microRNA的MRE的设计将非常耗时且耗费成本。结果在本文中，我们介绍了可用于设计甲型H1N1病毒基因片段中人类microRNA的MRE的计算流程。该流程的主要步骤包括找到可能的结合位点;使用miRNA靶标预测工具（miranda）在病毒序列中的人类microRNA的MRE，在不匹配的结合位置之间进行各种突变，计算结合能，得分，同一性以及根据改变的氨基酸物理性质改变的影响RNA水平的碱基，并优先确定突变的结合位点。人类microRNA hsa-miR-93的MRE排名最高，与以前的文献一致，而其他结果有待实验验证。为了使病毒学家容易地获得计算流程，我们还开发了MicroLive（MRE设计流程的网络服务器版本）以及米兰达预测的MRE数据库，该数据库包含7种RNA病毒（包括甲型流感，登革热，丙型肝炎，麻疹）的基因序列，腮腺炎，脊髓灰质炎病毒和狂犬病。用户可以使用MRE设计工具为输入的病毒序列设计特定人类microRNA的MRE，或优化系统上可用的七种病毒的经米兰达（Miranda）预测的MRE。同样，用户可以为多种人类microRNA设计不同数量的MRE，以调节活疫苗的衰减程度并降低逃逸突变体的可能性。结论MRE的计算设计有助于减少实验试验的时间和成本。尽管使用人microRNA和A型H1N1流感病毒已证明了这一流程，但可以将其灵活应用于其他宿主（例如动物）和目的病毒，以构建宿主特异性减毒活疫苗。同样，它可以被部署用于在癌症病毒治疗技术中工程化组织特异性溶瘤病毒。可从http://www.biotec.or.th/isl/microlive免费访问MicroLive Web服务器。

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