A novel enterovirus protein modulates infection in gut epithelial cells
A novel enterovirus protein modulates infection in gut epithelial cells
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一种新型肠道病毒蛋白调节肠上皮细胞感染
DOI：
10.1099/acmi.ac2019.po0129
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发表时间：
2019
影响因子：
--
通讯作者：
Lulla V
中科院分区：
文献类型：
--
作者：
Lulla V
肠道病毒包括包括脊髓灰质炎病毒在内的一大群哺乳动物病原体。人类的病理范围从亚临床到急性迟缓性瘫痪、心肌炎和脑膜炎。到目前为止，所有的肠道病毒蛋白都被认为是通过对编码在单个开放阅读框架(ORF)中的多蛋白进行蛋白水解性加工而来的。我们报道，许多肠道病毒基因组还含有一个上游ORF(UORF)，它受到强烈的纯化选择的影响。利用Echo病毒7和脊髓灰质炎病毒1，我们证实了uORF蛋白(UORF)在感染细胞中的表达。利用核糖体图谱(一种翻译核糖体的全球足迹技术)，我们还证明了uORF在主要人类肠道病毒物种的代表成员中的翻译，即肠道病毒A、B和C。在分化的人类肠道器官中，与野生型病毒相比，在感染的后期，膜相关的UP促进病毒释放，向上敲除的ECHO病毒减弱。因此，我们已经确定了一种以前未知的肠道病毒蛋白，它可以促进病毒在肠道上皮细胞中的生长-病毒最初入侵易感宿主的位置。这些发现颠覆了50年来肠病毒使用单一多蛋白基因表达策略的教条，并对理解肠道病毒的发病机制具有重要意义。
Enteroviruses comprise a large group of mammalian pathogens that includes poliovirus. Pathology in humans ranges from sub-clinical to acute flaccid paralysis, myocarditis and meningitis. Until now, all the enteroviral proteins were thought to derive from proteolytic processing of a polyprotein encoded in a single open reading frame (ORF). We report that many enterovirus genomes also harbor an upstream ORF (uORF) that is subject to strong purifying selection. Using echovirus 7 and poliovirus 1, we confirmed expression of uORF protein (UP) in infected cells. Using ribosome profiling (a technique for global footprinting of translating ribosomes), we also demonstrated translation of the uORF in representative members of the predominant human enterovirus species, namely Enterovirus A, B and C. In differentiated human intestinal organoids, UP-knockout echoviruses are attenuated compared to wild-type virus at late stages of infection where membrane-associated UP facilitates virus release. Thus we have identified a previously unknown enterovirus protein that facilitates virus growth in gut epithelial cells – the site of initial viral invasion into susceptible hosts. These findings overturn the 50-year-old dogma that enteroviruses use a single-polyprotein gene expression strategy, and have important implications for understanding enterovirus pathogenesis.