Southern University of Science and Technology School of Medicine, China.
Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
Brief Bioinform. 2021 Mar 22;22(2):1096-1105. doi: 10.1093/bib/bbab027.
Human coronaviruses (CoVs) can cause respiratory infection epidemics that sometimes expand into globally relevant pandemics. All human CoVs have sister strains isolated from animal hosts and seem to have an animal origin, yet the process of host jumping is largely unknown. RNA interference (RNAi) is an ancient mechanism in many eukaryotes to defend against viral infections through the hybridization of host endogenous small RNAs (miRNAs) with target sites in invading RNAs. Here, we developed a method to identify potential RNAi-sensitive sites in the viral genome and discovered that human-adapted coronavirus strains had deleted some of their sites targeted by miRNAs in human lungs when compared to their close zoonic relatives. We further confirmed using a phylogenetic analysis that the loss of RNAi-sensitive target sites could be a major driver of the host-jumping process, and adaptive mutations that lead to the loss-of-target might be as simple as point mutation. Up-to-date genomic data of severe acute respiratory syndrome coronavirus 2 and Middle-East respiratory syndromes-CoV strains demonstrate that the stress from host miRNA milieus sustained even after their epidemics in humans. Thus, this study illustrates a new mechanism about coronavirus to explain its host-jumping process and provides a novel avenue for pathogenesis research, epidemiological modeling, and development of drugs and vaccines against coronavirus, taking into consideration these findings.
人类冠状病毒（CoV）可引起呼吸道感染疫情，有时会扩展为全球相关的大流行。所有人类 CoV 都有从动物宿主中分离出来的姊妹株，似乎都有动物起源，但宿主跳跃的过程在很大程度上尚不清楚。RNA 干扰（RNAi）是许多真核生物抵御病毒感染的一种古老机制，通过宿主内源性小 RNA（miRNA）与入侵 RNA 中的靶位点杂交来实现。在这里，我们开发了一种识别病毒基因组中潜在 RNAi 敏感位点的方法，并发现与密切相关的人畜共患病原体相比，适应人类的冠状病毒株在其肺部中已经删除了一些被 miRNA 靶向的位点。我们进一步通过系统发育分析证实，RNAi 敏感靶位的丢失可能是宿主跳跃过程的主要驱动因素，而导致靶位丢失的适应性突变可能像点突变一样简单。目前严重急性呼吸综合征冠状病毒 2 株和中东呼吸综合征冠状病毒株的基因组数据表明，即使在人类流行之后，宿主 miRNA 环境的压力仍在持续。因此，本研究通过一种新机制阐释了冠状病毒的宿主跳跃过程，并为冠状病毒的发病机制研究、流行病学建模以及药物和疫苗的开发提供了新途径，在考虑到这些发现的情况下。
