Evolutionary Arms Race between Virus and Host Drives Genetic Diversity in Bat Severe Acute Respiratory Syndrome-Related Coronavirus Spike Genes.
Evolutionary Arms Race between Virus and Host Drives Genetic Diversity in Bat Severe Acute Respiratory Syndrome-Related Coronavirus Spike Genes.
复制标题
病毒与宿主之间的进化军备竞赛驱动蝙蝠严重急性呼吸系统综合症相关冠状病毒刺突基因的遗传多样性
DOI：
10.1128/jvi.00902-20
复制
发表时间：
2020-09-29
影响因子：
5.4
通讯作者：
Shi ZL
中科院分区：
文献类型：
--
作者：
Guo H;Hu BJ;Yang XL;Zeng LP;Li B;Ouyang S;Shi ZL
进化中的军备竞赛动态塑造了病毒及其受体的多样性。识别参与物种间传播的关键残基对于预测野生动物向人类的潜在病原体溢出具有重要意义。此前，我们已经在中国马蹄蝠中发现了遗传多样性的SARSR-CoV。在这里，我们展示了高度多态的ACE2在中国马蹄蝙蝠种群。这些ACE2变异体支持SARS-CoV和SARSR-CoV的感染，但与不同的Spike蛋白具有不同的结合亲和力。SARSR-CoV刺突与人ACE2具有较高的结合亲和力，表明这些病毒具有溢出人类的能力。ACE2和SARSR-CoV Spike蛋白界面上残基的积极选择表明它们之间存在长期和持续的共同进化动力学。对蝙蝠体内的这组病毒进行持续监测对于预防下一种类似SARS的疾病是必要的。摘要中华蝙蝠(Rhinolphus Sinicus)是严重急性呼吸综合征冠状病毒(SARS-CoV)的宿主，携带着许多与SARS相关的蝙蝠冠状病毒(SARSR-CoV)，具有很高的遗传多样性，特别是在棘突基因上。尽管有这些变化，一些蝙蝠SARSR冠状病毒可以利用人类SARS冠状病毒受体的同源基因-血管紧张素转换酶2(ACE2)-进入。推测BAT ACE2和SARSR冠状病毒刺突蛋白之间的相互作用驱动了多样性。在这里，我们鉴定了一系列与SARS冠状病毒刺突蛋白相互作用的中华乳杆菌ACE2变异体，它们具有一些多态位点。携带不同刺突蛋白的伪病毒或SARSR-CoV在瞬时表达BAT ACE2变异体的细胞中表现出不同的感染效率。SARS-CoV和SARSR-CoV刺突蛋白与蝙蝠和人类受体分子的结合亲和力分析结果一致。所有测试的BAT SARSR-CoV刺突蛋白与人ACE2的结合亲和力均高于与BAT ACE2的结合亲和力，但与人ACE2的结合亲和力比SARS-CoV刺突蛋白低10倍。结构模拟表明，SPEKE和ACE2结合亲和力的差异可能是由于这两个分子界面上的一些关键残基的改变造成的。分子进化分析表明，一些关键残基处于正选择状态。这些结果表明，SARSR-CoV Spike蛋白和中华乳杆菌ACE2可能随着时间的推移而共同进化，并经历了来自彼此的选择压力，触发了进化的军备竞赛动态。重要性演变中的军备竞赛动态塑造了病毒及其受体的多样性。识别参与物种间传播的关键残基对于预测野生动物向人类的潜在病原体溢出具有重要意义。此前，我们已经在中国马蹄蝠中发现了遗传多样性的SARSR-CoV。在这里，我们展示了高度多态的ACE2在中国马蹄蝙蝠种群。这些ACE2变异体支持SARS-CoV和SARSR-CoV的感染，但与不同的Spike蛋白具有不同的结合亲和力。SARSR-CoV刺突与人ACE2具有较高的结合亲和力，表明这些病毒具有溢出人类的能力。ACE2和SARSR-CoV Spike蛋白界面上残基的积极选择表明它们之间存在长期和持续的共同进化动力学。对蝙蝠体内的这组病毒进行持续监测对于预防下一种类似SARS的疾病是必要的。
Evolutionary arms race dynamics shape the diversity of viruses and their receptors. Identification of key residues which are involved in interspecies transmission is important to predict potential pathogen spillover from wildlife to humans. Previously, we have identified genetically diverse SARSr-CoVs in Chinese horseshoe bats. Here, we show the highly polymorphic ACE2 in Chinese horseshoe bat populations. These ACE2 variants support SARS-CoV and SARSr-CoV infection but with different binding affinities to different spike proteins. The higher binding affinity of SARSr-CoV spike to human ACE2 suggests that these viruses have the capacity for spillover to humans. The positive selection of residues at the interface between ACE2 and SARSr-CoV spike protein suggests long-term and ongoing coevolutionary dynamics between them. Continued surveillance of this group of viruses in bats is necessary for the prevention of the next SARS-like disease. ABSTRACT The Chinese horseshoe bat (Rhinolophus sinicus), reservoir host of severe acute respiratory syndrome coronavirus (SARS-CoV), carries many bat SARS-related CoVs (SARSr-CoVs) with high genetic diversity, particularly in the spike gene. Despite these variations, some bat SARSr-CoVs can utilize the orthologs of the human SARS-CoV receptor, angiotensin-converting enzyme 2 (ACE2), for entry. It is speculated that the interaction between bat ACE2 and SARSr-CoV spike proteins drives diversity. Here, we identified a series of R. sinicus ACE2 variants with some polymorphic sites involved in the interaction with the SARS-CoV spike protein. Pseudoviruses or SARSr-CoVs carrying different spike proteins showed different infection efficiencies in cells transiently expressing bat ACE2 variants. Consistent results were observed by binding affinity assays between SARS-CoV and SARSr-CoV spike proteins and receptor molecules from bats and humans. All tested bat SARSr-CoV spike proteins had a higher binding affinity to human ACE2 than to bat ACE2, although they showed a 10-fold lower binding affinity to human ACE2 compared with that of their SARS-CoV counterpart. Structure modeling revealed that the difference in binding affinity between spike and ACE2 might be caused by the alteration of some key residues in the interface of these two molecules. Molecular evolution analysis indicates that some key residues were under positive selection. These results suggest that the SARSr-CoV spike protein and R. sinicus ACE2 may have coevolved over time and experienced selection pressure from each other, triggering the evolutionary arms race dynamics. IMPORTANCE Evolutionary arms race dynamics shape the diversity of viruses and their receptors. Identification of key residues which are involved in interspecies transmission is important to predict potential pathogen spillover from wildlife to humans. Previously, we have identified genetically diverse SARSr-CoVs in Chinese horseshoe bats. Here, we show the highly polymorphic ACE2 in Chinese horseshoe bat populations. These ACE2 variants support SARS-CoV and SARSr-CoV infection but with different binding affinities to different spike proteins. The higher binding affinity of SARSr-CoV spike to human ACE2 suggests that these viruses have the capacity for spillover to humans. The positive selection of residues at the interface between ACE2 and SARSr-CoV spike protein suggests long-term and ongoing coevolutionary dynamics between them. Continued surveillance of this group of viruses in bats is necessary for the prevention of the next SARS-like disease.