Department of Electrical and Computer Engineering, McGill University, 755, McConnell Engineering Building, 3480 University Street, Montreal, QC, H3A 0E9, Canada.
The Meakins-Christie Laboratories at the Research Institute of McGill University Heath Centre (RI-MUHC), McGill University, E M3.2244, 1001 Décarie, Montreal, QC, H4A 3J1, Canada.
Sci Rep. 2021 Dec 14;11(1):23928. doi: 10.1038/s41598-021-03309-5.
Identification of transcriptional regulatory mechanisms and signaling networks involved in the response of host cells to infection by SARS-CoV-2 is a powerful approach that provides a systems biology view of gene expression programs involved in COVID-19 and may enable the identification of novel therapeutic targets and strategies to mitigate the impact of this disease. In this study, our goal was to identify a transcriptional regulatory network that is associated with gene expression changes between samples infected by SARS-CoV-2 and those that are infected by other respiratory viruses to narrow the results on those enriched or specific to SARS-CoV-2. We combined a series of recently developed computational tools to identify transcriptional regulatory mechanisms involved in the response of epithelial cells to infection by SARS-CoV-2, and particularly regulatory mechanisms that are specific to this virus when compared to other viruses. In addition, using network-guided analyses, we identified kinases associated with this network. The results identified pathways associated with regulation of inflammation (MAPK14) and immunity (BTK, MBX) that may contribute to exacerbate organ damage linked with complications of COVID-19. The regulatory network identified herein reflects a combination of known hits and novel candidate pathways supporting the novel computational pipeline presented herein to quickly narrow down promising avenues of investigation when facing an emerging and novel disease such as COVID-19.
鉴定宿主细胞对 SARS-CoV-2 感染反应中涉及的转录调控机制和信号网络是一种强大的方法，它提供了 COVID-19 相关基因表达程序的系统生物学观点，并可能有助于鉴定新的治疗靶点和策略来减轻这种疾病的影响。在这项研究中，我们的目标是鉴定一个与 SARS-CoV-2 感染样本和其他呼吸道病毒感染样本之间基因表达变化相关的转录调控网络，以缩小结果范围，使其富集或特定于 SARS-CoV-2。我们结合了一系列最近开发的计算工具，来鉴定上皮细胞对 SARS-CoV-2 感染反应中涉及的转录调控机制，特别是与其他病毒相比，SARS-CoV-2 特有的调控机制。此外，我们还使用网络引导分析鉴定了与该网络相关的激酶。研究结果确定了与炎症（MAPK14）和免疫（BTK、MBX）调节相关的途径，这些途径可能会加重与 COVID-19 并发症相关的器官损伤。本文鉴定的调控网络反映了已知靶点和新候选途径的组合，支持本文提出的新颖计算管道，当面临 COVID-19 等新兴和新型疾病时，可以快速缩小有前途的研究途径。
