像单链RNA病毒一样,SARS-CoV-2劫持宿主转录机制以进行自身复制。许多传统的基于差异基因表达的研究已经检查了由SARS-CoV-2感染引起的各种临床症状。病毒,另一方面,也会影响主机拼接机器,导致宿主转录失调,这可能导致不同的临床结果。因此,在这项研究中,我们对125例住院COVID-19患者进行了宿主转录组测序,以了解轻度,中度,严重,和死亡率。我们进行了转录水平差异表达分析,调查了不同的同工型用法,查看差异表达转录本(DET)内的剪接模式,并阐明了可能的基因组调控特征。我们的DTE分析显示,在COVID-19死亡率患者中,差异表达的蛋白质编码转录本的转录本长度和多样性减少以及启动子位点使用改变的证据。我们还研究了驱动可变剪接的潜在机制,并发现了启动子区域中重复序列的引人注目的差异富集和差异表达转录本的剪接位点附近的SINE(Alu)的特异性富集。这些发现表明,重复介导的选择性剪接的合理调节是COVID-19疾病严重程度的潜在调节剂。在这项工作中,我们强调了可变剪接在影响COVID-19疾病严重程度亚表型中几乎未阐明的功能作用,临床结果,及其推定机制。重要性在COVID-19大流行期间报告的广泛临床症状固有地突出了影响SARS-CoV-2感染进展和预后的众多因素。虽然一些研究已经调查了宿主反应并发现严重感染期间的免疫失调,他们中的大多数都有一个共同的主题,那就是只关注基因水平。病毒,尤其是RNA病毒,以劫持主机拼接机器为自己的扩散而闻名,无意中给宿主转录组带来了压力,暴露宿主对病原体攻击的反应的另一面。因此,在这项研究中,我们在转录水平检查宿主反应,以发现转录差异,最终导致差异基因水平表达。重要的是,这项研究强调了COVID-19死亡患者的转录物多样性减少,以及启动子区和剪接位点附近差异丰富的重复元件对转录的可能调控,与差异表达的同种型一起,具有阐明疾病严重程度和结局的潜力。
Like single-stranded RNA viruses, SARS-CoV-2 hijacks the host transcriptional machinery for its own replication. Numerous traditional differential gene expression-based investigations have examined the diverse clinical symptoms caused by SARS-CoV-2 infection. The virus, on the other hand, also affects the host splicing machinery, causing host transcriptional dysregulation, which can lead to diverse clinical outcomes. Hence, in this study, we performed host transcriptome sequencing of 125 hospital-admitted COVID-19 patients to understand the transcriptomic differences between the severity sub-phenotypes of mild, moderate, severe, and mortality. We performed transcript-level differential expression analysis, investigated differential isoform usage, looked at the splicing patterns within the differentially expressed transcripts (DET), and elucidated the possible genome regulatory features. Our DTE analysis showed evidence of diminished transcript length and diversity as well as altered promoter site usage in the differentially expressed protein-coding transcripts in the COVID-19 mortality patients. We also investigated the potential mechanisms driving the alternate splicing and discovered a compelling differential enrichment of repeats in the promoter region and a specific enrichment of SINE (Alu) near the splicing sites of differentially expressed transcripts. These findings suggested a repeat-mediated plausible regulation of alternative splicing as a potential modulator of COVID-19 disease severity. In this work, we emphasize the role of scarcely elucidated functional role of alternative splicing in influencing COVID-19 disease severity sub-phenotypes, clinical outcomes, and its putative mechanism. IMPORTANCE The wide range of clinical symptoms reported during the COVID-19 pandemic inherently highlights the numerous factors that influence the progression and prognosis of SARS-CoV-2 infection. While several studies have investigated the host response and discovered immunological dysregulation during severe infection, most of them have the common theme of focusing only up to the gene level. Viruses, especially RNA viruses, are renowned for hijacking the host splicing machinery for their own proliferation, which inadvertently puts pressure on the host transcriptome, exposing another side of the host response to the pathogen challenge. Therefore, in this study, we examine host response at the transcript-level to discover a transcriptional difference that culminates in differential gene-level expression. Importantly, this study highlights diminished transcript diversity and possible regulation of transcription by differentially abundant repeat elements near the promoter region and splicing sites in COVID-19 mortality patients, which together with differentially expressed isoforms hold the potential to elaborate disease severity and outcome.