Selinger Christian, Tisoncik-Go Jennifer, Menachery Vineet D, Agnihothram Sudhakar, Law G Lynn, Chang Jean, Kelly Sara M, Sova Pavel, Baric Ralph S, Katze Michael G
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA.
Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
BMC Genomics. 2014 Dec 22;15(1):1161. doi: 10.1186/1471-2164-15-1161.
The recent emergence of a novel coronavirus in the Middle East (designated MERS-CoV) is a reminder of the zoonotic and pathogenic potential of emerging coronaviruses in humans. Clinical features of Middle East respiratory syndrome (MERS) include atypical pneumonia and progressive respiratory failure that is highly reminiscent of severe acute respiratory syndrome (SARS) caused by SARS-CoV. The host response is a key component of highly pathogenic respiratory virus infection. Here, we computationally analyzed gene expression changes in a human airway epithelial cell line infected with two genetically distinct MERS-CoV strains obtained from human patients, MERS-CoV SA 1 and MERS-CoV Eng 1.
Using topological techniques, including persistence homology and filtered clustering, we performed a comparative transcriptional analysis of human Calu-3 cell host responses to the different MERS-CoV strains, with MERS-CoV Eng 1 inducing early kinetic changes, between 3 and 12 hours post infection, compared to MERS-CoV SA 1. Robust transcriptional changes distinguished the two MERS-CoV strains predominantly at the late time points. Combining statistical analysis of infection and cytokine-stimulated Calu-3 transcriptomics, we identified differential innate responses, including up-regulation of extracellular remodeling genes following MERS-CoV Eng 1 infection and differential pro-inflammatory responses.
Through our genomics-based approach, we found topological differences in the kinetics and magnitude of the host response to MERS-CoV SA 1 and MERS-CoV Eng 1, with differential expression of innate immune and pro-inflammatory responsive genes as a result of IFN, TNF and IL-1α signaling. Predicted activation for STAT3 mediating gene expression relevant for epithelial cell-to-cell adherens and junction signaling in MERS-CoV Eng 1 infection suggest that these transcriptional differences may be the result of amino acid differences in viral proteins known to modulate innate immunity during MERS-CoV infection.
中东地区最近出现的一种新型冠状病毒（命名为MERS-CoV）提醒人们，新发冠状病毒对人类具有人畜共患和致病潜力。中东呼吸综合征（MERS）的临床特征包括非典型肺炎和进行性呼吸衰竭，这与严重急性呼吸综合征（SARS）由SARS-CoV引起的情况极为相似。宿主反应是高致病性呼吸道病毒感染的关键组成部分。在此，我们通过计算分析了人呼吸道上皮细胞系感染从人类患者分离得到的两种基因不同的MERS-CoV毒株（MERS-CoV SA 1和MERS-CoV Eng 1）后的基因表达变化。
利用包括持久同调与过滤聚类在内的拓扑技术，我们对人Calu-3细胞对不同MERS-CoV毒株的宿主反应进行了比较转录分析，结果显示与MERS-CoV SA 1相比，MERS-CoV Eng 1在感染后3至12小时诱导了早期动力学变化。在感染后期，强大的转录变化主要区分了这两种MERS-CoV毒株。结合对感染和细胞因子刺激的Calu-3转录组学的统计分析，我们确定了不同的先天反应，包括MERS-CoV Eng 1感染后细胞外重塑基因的上调以及不同的促炎反应。
通过基于基因组学的方法，我们发现宿主对MERS-CoV SA 1和MERS-CoV Eng 1反应的动力学和强度存在拓扑差异，由于IFN、TNF和IL-1α信号传导，先天免疫和促炎反应相关基因存在差异表达。预测STAT3在MERS-CoV Eng 1感染中介导与上皮细胞间黏附及连接信号相关的基因表达激活，表明这些转录差异可能是MERS-CoV感染期间已知可调节先天免疫的病毒蛋白氨基酸差异的结果。
