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Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2 [Microbiology]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2021-03-23 , DOI: 10.1073/pnas.2025373118
Yinghui Liu 1 , Gaowei Hu 2 , Yuyan Wang 2 , Wenlin Ren 1 , Xiaomin Zhao 1 , Fansen Ji 1 , Yunkai Zhu 2 , Fei Feng 2 , Mingli Gong 1 , Xiaohui Ju 1 , Yuanfei Zhu 2 , Xia Cai 2 , Jun Lan 3 , Jianying Guo 1 , Min Xie 1 , Lin Dong 1 , Zihui Zhu 1 , Jie Na 1 , Jianping Wu 4, 5 , Xun Lan 1 , Youhua Xie 2 , Xinquan Wang 3, 6 , Zhenghong Yuan 7 , Rong Zhang 7 , Qiang Ding 6, 8
Affiliation  

The pandemic of COVID-19, caused by SARS-CoV-2, is a major global health threat. Epidemiological studies suggest that bats (Rhinolophus affinis) are the natural zoonotic reservoir for SARS-CoV-2. However, the host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. The interaction of coronavirus with its host receptor is a key genetic determinant of host range and cross-species transmission. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor to enter host cells in a species-dependent manner. In this study, we characterized the ability of ACE2 from diverse species to support viral entry. By analyzing the conservation of five residues in two virus-binding hotspots of ACE2 (hotspot 31Lys and hotspot 353Lys), we predicted 80 ACE2 proteins from mammals that could potentially mediate SARS-CoV-2 entry. We chose 48 ACE2 orthologs among them for functional analysis, and showed that 44 of these orthologs—including domestic animals, pets, livestock, and animals commonly found in zoos and aquaria—could bind the SARS-CoV-2 spike protein and support viral entry. In contrast, New World monkey ACE2 orthologs could not bind the SARS-CoV-2 spike protein and support viral entry. We further identified the genetic determinant of New World monkey ACE2 that restricts viral entry using genetic and functional analyses. These findings highlight a potentially broad host tropism of SARS-CoV-2 and suggest that SARS-CoV-2 might be distributed much more widely than previously recognized, underscoring the necessity to monitor susceptible hosts to prevent future outbreaks.



中文翻译:

病毒受体 ACE2 直系同源物的功能和遗传分析揭示了 SARS-CoV-2 的广泛潜在宿主范围 [微生物学]

由 SARS-CoV-2 引起的 COVID-19 大流行是一个主要的全球健康威胁。流行病学研究表明,蝙蝠(Rhinolophus affinis) 是 SARS-CoV-2 的天然人畜共患病宿主。然而,SARS-CoV-2 的宿主范围和促进其传播给人类的中间宿主仍然未知。冠状病毒与其宿主受体的相互作用是宿主范围和跨物种传播的关键遗传决定因素。SARS-CoV-2 使用血管紧张素转换酶 2 (ACE2) 作为受体以物种依赖性方式进入宿主细胞。在这项研究中,我们描述了来自不同物种的 ACE2 支持病毒进入的能力。通过分析 ACE2 的两个病毒结合热点(热点 31Lys 和热点 353Lys)中五个残基的保守性,我们预测了来自哺乳动物的 80 种 ACE2 蛋白可能介导 SARS-CoV-2 进入。我们从中选择了 48 个 ACE2 直系同源物进行功能分析,并表明,其中 44 种直系同源物——包括家畜、宠物、牲畜和动物园和水族馆中常见的动物——可以结合 SARS-CoV-2 刺突蛋白并支持病毒进入。相比之下,新世界猴 ACE2 直系同源物不能结合 SARS-CoV-2 刺突蛋白并支持病毒进入。我们使用遗传和功能分析进一步确定了限制病毒进入的新世界猴 ACE2 的遗传决定因素。这些发现突出了 SARS-CoV-2 潜在的广泛宿主嗜性,并表明 SARS-CoV-2 的分布范围可能比以前认识到的要广泛得多,强调了监测易感宿主以防止未来爆发的必要性。新世界猴 ACE2 直系同源物无法结合 SARS-CoV-2 刺突蛋白并支持病毒进入。我们使用遗传和功能分析进一步确定了限制病毒进入的新世界猴 ACE2 的遗传决定因素。这些发现突出了 SARS-CoV-2 潜在的广泛宿主嗜性,并表明 SARS-CoV-2 的分布范围可能比以前认识到的要广泛得多,强调了监测易感宿主以防止未来爆发的必要性。新世界猴 ACE2 直系同源物无法结合 SARS-CoV-2 刺突蛋白并支持病毒进入。我们使用遗传和功能分析进一步确定了限制病毒进入的新世界猴 ACE2 的遗传决定因素。这些发现突出了 SARS-CoV-2 潜在的广泛宿主嗜性,并表明 SARS-CoV-2 的分布范围可能比以前认识到的要广泛得多,强调了监测易感宿主以防止未来爆发的必要性。

更新日期:2021-03-04
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