Harnessing endogenous miRNAs to control virus tissue tropism as a strategy for developing attenuated virus vaccines.
Harnessing endogenous miRNAs to control virus tissue tropism as a strategy for developing attenuated virus vaccines.
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DOI：
10.1016/j.chom.2008.08.003
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发表时间：
2008-09-11
影响因子：
30.3
通讯作者：
Andino, Raul
中科院分区：
文献类型：
--
作者：
Barnes, Dwight;Kunitomi, Mark;Vignuzzi, Marco;Saksela, Kalle;Andino, Raul
减毒活疫苗仍然是预防病毒感染最安全、最具成本效益的干预措施。由于活疫苗株是凭经验产生的，减毒的基础通常不明确，许多重要的病毒缺乏有效的活疫苗。在这里，我们提出了一个合理设计安全有效的活疫苗的一般策略，利用基于microRNA的基因沉默机制来控制病毒复制。以脊髓灰质炎病毒为模型，我们证明了在病毒基因组中插入小的miRNA同源序列可以限制其组织嗜性，从而防止致病性并产生减毒病毒株。脊髓灰质炎病毒株被改造成为神经元特异性miRNA的靶点，失去了在中枢神经系统中复制的能力，导致感染动物的神经毒力显著减弱。重要的是，这些病毒保留了在非神经元组织中复制的能力。结果，这些工程化的miRNA调节的病毒在小鼠中引发了强烈的保护性免疫而不产生疾病。
Live, attenuated vaccines remain the safest, most cost-effective intervention against viral infections. Because live vaccine strains are generated empirically and the basis for attenuation is usually ill defined, many important viruses lack an efficient live vaccine. Here, we present a general strategy for the rational design of safe and effective live vaccines that harnesses the microRNA-based gene silencing machinery to control viral replication. Using poliovirus as a model, we demonstrate that insertion of small miRNA homology sequences into a viral genome can restrict its tissue tropism, thereby preventing pathogenicity and yielding an attenuated viral strain. Poliovirus strains engineered to become targets of neuronal-specific miRNAs lost their ability to replicate in the central nervous system, leading to significant attenuation of neurovirulence in infected animals. Importantly, these viruses retained the ability to replicate in non-neuronal tissues. As a result, these engineered miRNA-regulated viruses elicited strong protective immunity in mice without producing disease.
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