Transcriptional response of signalling pathways to SARS-CoV-2 infection in normal human bronchial epithelial cells
Transcriptional response of signalling pathways to SARS-CoV-2 infection in normal human bronchial epithelial cells
复制标题
正常人支气管上皮细胞中信号通路对 SARS-CoV-2 感染的转录反应
DOI：
10.1101/2020.06.20.163006
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Pınar Pir
中科院分区：
文献类型：
--
作者：
Ak Enes;Pınar Pir
导致新冠肺炎的病原体SARS-CoV-2病毒于2019年在武汉地区中国出现，感染了400多万人，截至2020年5月，全球至少30万患者死亡。识别SARS-CoV-2对病毒感染的细胞反应机制可能有助于阐明疾病的进展，指明潜在的药物靶点，并使设计新的测试方法成为可能。在这项研究中，我们分析了正常人支气管上皮细胞(NHBE)对SARS-CoV-2感染的转录反应，并比较了对H1N1感染的反应。比较模拟感染和SARS-CoV-2感染24小时后NHBE细胞的转录组发现，大多数感染反应的基因上调(320个基因)而不是下调(115个基因)。虽然上调的基因在与病毒反应相关的信号通路中丰富，但下调的基因与肾脏发育有关。我们将上调的基因定位在KEGG通路上，以确定介导反应的机制。我们发现典型的核因子κB、肿瘤坏死因子和白介素17通路显著上调，并通过正反馈环汇聚到核因子κB通路。尽管病毒进入蛋白ACE2在NHBE细胞中低表达，但病原体反应通路在感染后24小时内被强烈激活。我们的结果还表明，免疫反应系统在感染的早期阶段被激活，并由一系列信号通路协调。最后，我们在NHBE细胞中比较了SARS-CoV-2转录反应和H1N1反应，以阐明该反应的病毒特异性和NHBE细胞表达的病毒特异性胞外蛋白。
SARS-CoV-2 virus, the pathogen that causes Covid-19 disease, emerged in Wuhan region in China in 2019, infected more than 4M people and is responsible for death of at least 300K patients globally as of May 2020. Identification of the cellular response mechanisms to viral infection by SARS-CoV-2 may shed light on progress of the disease, indicate potential drug targets, and make design of new test methods possible. In this study, we analysed transcriptomic response of normal human bronchial epithelial cells (NHBE) to SARS-CoV-2 infection and compared the response to H1N1 infection. Comparison of transcriptome of NHBE cells 24 hours after mock-infection and SARS-CoV-2 infection demonstrated that most genes that respond to infection were upregulated (320 genes) rather than being downregulated (115 genes).While upregulated genes were enriched in signalling pathways related to virus response, downregulated genes are related to kidney development. We mapped the upregulated genes on KEGG pathways to identify the mechanisms that mediate the response. We identified canonical NFκB, TNF and IL-17 pathways to be significantly upregulated and to converge to NFκB pathway via positive feedback loops. Although virus entry protein ACE2 has low expression in NHBE cells, pathogen response pathways are strongly activated within 24 hours of infection. Our results also indicate that immune response system is activated at the early stage of the infection and orchestrated by a crosstalk of signalling pathways. Finally, we compared transcriptomic SARS-CoV-2 response to H1N1 response in NHBE cells to elucidate the virus specificity of the response and virus specific extracellular proteins expressed by NHBE cells.