Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China.
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Biosafety Level 3 Laboratory, Fudan University, Shanghai, China.
PLoS Pathog. 2021 Mar 24;17(3):e1009392. doi: 10.1371/journal.ppat.1009392. eCollection 2021 Mar.
Coronavirus interaction with its viral receptor is a primary genetic determinant of host range and tissue tropism. SARS-CoV-2 utilizes ACE2 as the receptor to enter host cell in a species-specific manner. We and others have previously shown that ACE2 orthologs from New World monkey, koala and mouse cannot interact with SARS-CoV-2 to mediate viral entry, and this defect can be restored by humanization of the restrictive residues in New World monkey ACE2. To better understand the genetic determinants behind the ability of ACE2 orthologs to support viral entry, we compared koala and mouse ACE2 sequences with that of human and identified the key residues in koala and mouse ACE2 that restrict viral receptor activity. Humanization of these critical residues rendered both koala and mouse ACE2 capable of binding the spike protein and facilitating viral entry. Our study shed more lights into the genetic determinants of ACE2 as the functional receptor of SARS-CoV-2, which facilitates our understanding of viral entry.
冠状病毒与其病毒受体的相互作用是宿主范围和组织嗜性的主要遗传决定因素。SARS-CoV-2 以物种特异性的方式利用 ACE2 作为受体进入宿主细胞。我们和其他人之前已经表明，来自新世界猴、考拉和小鼠的 ACE2 同源物不能与 SARS-CoV-2 相互作用以介导病毒进入，并且可以通过在新世界猴 ACE2 中赋予限制残基的人源化来恢复这种缺陷。为了更好地理解 ACE2 同源物支持病毒进入的能力背后的遗传决定因素，我们比较了考拉和小鼠 ACE2 序列与人类的序列，并确定了限制病毒受体活性的考拉和小鼠 ACE2 中的关键残基。将这些关键残基人源化使考拉和小鼠 ACE2 都能够结合刺突蛋白并促进病毒进入。我们的研究更深入地了解了 ACE2 作为 SARS-CoV-2 的功能性受体的遗传决定因素，这有助于我们理解病毒进入。
