Khan Md Abdullah-Al-Kamran, Sany Md Rabi Us, Islam Md Shafiqul, Islam Abul Bashar Mir Md Khademul
Department of Mathematics and Natural Sciences, BRAC University, Dhaka, Bangladesh.
Department of Genetic Engineering & Biotechnology, University of Dhaka, Dhaka, Bangladesh.
Front Genet. 2020 Jul 10;11:765. doi: 10.3389/fgene.2020.00765. eCollection 2020.
A detailed understanding of the molecular mechanism of SARS-CoV-2 pathogenesis is still elusive, and there is a need to address its deadly nature and to design effective therapeutics. Here, we present a study that elucidates the interplay between the SARS-CoV and SARS-CoV-2 viruses' and host's miRNAs, an epigenetic regulator, as a mode of pathogenesis; and we explored how the SARS-CoV and SARS-CoV-2 infections differ in terms of their miRNA-mediated interactions with the host and the implications this has in terms of disease complexity. We have utilized computational approaches to predict potential host and viral miRNAs and their possible roles in different important functional pathways. We have identified several putative host antiviral miRNAs that can target the SARS viruses and also predicted SARS viruses-encoded miRNAs targeting host genes. predicted targets were also integrated with SARS-infected human cell microarray and RNA-seq gene expression data. A comparison between the host miRNA binding profiles on 67 different SARS-CoV-2 genomes from 24 different countries with respective country's normalized death count surprisingly uncovered some miRNA clusters, which are associated with increased death rates. We have found that induced cellular miRNAs can be both a boon and a bane to the host immunity, as they have possible roles in neutralizing the viral threat; conversely, they can also function as proviral factors. On the other hand, from over representation analysis, our study revealed that although both SARS-CoV and SARS-CoV-2 viral miRNAs could target broad immune-signaling pathways; only some of the SARS-CoV-2 miRNAs are found to uniquely target some immune-signaling pathways, such as autophagy, IFN-I signaling, etc., which might suggest their immune-escape mechanisms for prolonged latency inside some hosts without any symptoms of COVID-19. Furthermore, SARS-CoV-2 can modulate several important cellular pathways that might lead to the increased anomalies in patients with comorbidities like cardiovascular diseases, diabetes, breathing complications, etc. This might suggest that miRNAs can be a key epigenetic modulator behind the overcomplications amongst the COVID-19 patients. Our results support that miRNAs of host and SARS-CoV-2 can indeed play a role in the pathogenesis which can be further concluded with more experiments. These results will also be useful in designing RNA therapeutics to alleviate the complications from COVID-19.
对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）发病机制的分子机制仍缺乏详细了解，因此有必要探究其致命性并设计有效的治疗方法。在此，我们展示了一项研究，该研究阐明了SARS-CoV和SARS-CoV-2病毒与宿主的微小RNA（miRNA，一种表观遗传调节因子）之间的相互作用，以此作为一种发病机制模式；并且我们探讨了SARS-CoV和SARS-CoV-2感染在通过miRNA介导与宿主相互作用方面的差异以及这对疾病复杂性的影响。我们利用计算方法预测潜在的宿主和病毒miRNA及其在不同重要功能途径中的可能作用。我们鉴定了几种可能靶向SARS病毒的宿主抗病毒miRNA，还预测了SARS病毒编码的靶向宿主基因的miRNA。预测的靶点还与感染SARS的人类细胞微阵列和RNA测序基因表达数据进行了整合。将来自24个不同国家的67个不同SARS-CoV-2基因组上的宿主miRNA结合谱与各自国家的标准化死亡人数进行比较，令人惊讶地发现了一些与死亡率增加相关的miRNA簇。我们发现，诱导产生的细胞miRNA对宿主免疫可能既是福音也是祸根，因为它们可能在中和病毒威胁中发挥作用；相反，它们也可能充当病毒前体因子。另一方面，通过过表达分析，我们的研究表明，虽然SARS-CoV和SARS-CoV-2病毒的miRNA都可以靶向广泛的免疫信号通路；但仅发现一些SARS-CoV-2的miRNA独特地靶向某些免疫信号通路，如自噬、I型干扰素信号等，这可能表明它们在一些宿主内长期潜伏且无COVID-19任何症状的免疫逃逸机制。此外，SARS-CoV-2可以调节几个重要的细胞途径，这可能导致患有心血管疾病、糖尿病、呼吸并发症等合并症的患者出现更多异常。这可能表明miRNA可能是COVID-19患者出现过度并发症背后的关键表观遗传调节因子。我们的结果支持宿主和SARS-CoV-2的miRNA确实可以在发病机制中发挥作用，这一点可通过更多实验进一步证实。这些结果对于设计RNA疗法以减轻COVID-19的并发症也将是有用的。
