Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus.
Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus.
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DOI：
10.1128/mbio.00165-13
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发表时间：
2013-04-30
期刊：
影响因子：
6.4
通讯作者：
Katze MG
中科院分区：
文献类型：
--
作者：
Josset L;Menachery VD;Gralinski LE;Agnihothram S;Sova P;Carter VS;Yount BL;Graham RL;Baric RS;Katze MG
一种新型人类冠状病毒（HCoV - EMC）近期在中东被确认为一种严重急性呼吸综合征（SARS）的病原体，该疾病类似于由SARS冠状病毒（SARS - CoV）引起的疾病。尽管这两种病毒都源自冠状病毒家族，但它们在基因上是不同的，且不使用相同的受体。在此，我们研究了HCoV - EMC和SARS - CoV在感染人肺上皮细胞系后是否会诱导相似或不同的宿主反应。HCoV - EMC在Calu - 3细胞中的复制效率与SARS - CoV相同，并且在感染后12小时之前诱导的转录组变化极小。在感染后期，HCoV - EMC对宿主转录组造成了大规模的失调，其程度远大于SARS - CoV。两种病毒都诱导了模式识别受体和白细胞介素17（IL - 17）通路的相似激活，但HCoV - EMC特异性地下调了抗原呈递通路内的几个基因的表达，包括I型和II型主要组织相容性复合体（MHC）基因。这可能对宿主产生适应性宿主反应的能力产生重要影响。在HCoV - EMC感染过程中，有一组独特的207个基因在早期且贯穿整个感染过程持续失调，并且被用于计算机筛选以预测潜在的抗病毒化合物，包括激酶抑制剂和糖皮质激素。总体而言，HCoV - EMC和SARS - CoV引发了不同的宿主基因表达反应，这可能影响体内发病机制，并可为针对这种新出现病毒的治疗策略提供方向。
一种导致人类致命呼吸道感染的新型冠状病毒的发现，引发了人们对可能发生类似于SARS - CoV所致的严重呼吸道感染广泛爆发的担忧。通过使用人肺上皮细胞系和全转录组分析，我们确定了HCoV - EMC和SARS - CoV之间宿主反应的差异。这使得能够快速评估病毒特性以及预测人类对HCoV - EMC和SARS - CoV临床反应可能存在的差异的能力。我们利用这些信息来预测针对HCoV - EMC的潜在有效药物，这种方法可更广泛地用于在未来疾病爆发时确定候选治疗药物。这些数据将有助于提出假设，并在这种新病毒的特征描述方面取得快速进展。
A novel human coronavirus (HCoV-EMC) was recently identified in the Middle East as the causative agent of a severe acute respiratory syndrome (SARS) resembling the illness caused by SARS coronavirus (SARS-CoV). Although derived from the CoV family, the two viruses are genetically distinct and do not use the same receptor. Here, we investigated whether HCoV-EMC and SARS-CoV induce similar or distinct host responses after infection of a human lung epithelial cell line. HCoV-EMC was able to replicate as efficiently as SARS-CoV in Calu-3 cells and similarly induced minimal transcriptomic changes before 12 h postinfection. Later in infection, HCoV-EMC induced a massive dysregulation of the host transcriptome, to a much greater extent than SARS-CoV. Both viruses induced a similar activation of pattern recognition receptors and the interleukin 17 (IL-17) pathway, but HCoV-EMC specifically down-regulated the expression of several genes within the antigen presentation pathway, including both type I and II major histocompatibility complex (MHC) genes. This could have an important impact on the ability of the host to mount an adaptive host response. A unique set of 207 genes was dysregulated early and permanently throughout infection with HCoV-EMC, and was used in a computational screen to predict potential antiviral compounds, including kinase inhibitors and glucocorticoids. Overall, HCoV-EMC and SARS-CoV elicit distinct host gene expression responses, which might impact in vivo pathogenesis and could orient therapeutic strategies against that emergent virus. Identification of a novel coronavirus causing fatal respiratory infection in humans raises concerns about a possible widespread outbreak of severe respiratory infection similar to the one caused by SARS-CoV. Using a human lung epithelial cell line and global transcriptomic profiling, we identified differences in the host response between HCoV-EMC and SARS-CoV. This enables rapid assessment of viral properties and the ability to anticipate possible differences in human clinical responses to HCoV-EMC and SARS-CoV. We used this information to predict potential effective drugs against HCoV-EMC, a method that could be more generally used to identify candidate therapeutics in future disease outbreaks. These data will help to generate hypotheses and make rapid advancements in characterizing this new virus.