Broad and Differential Animal Angiotensin-Converting Enzyme 2 Receptor Usage by SARS-CoV-2
Broad and Differential Animal Angiotensin-Converting Enzyme 2 Receptor Usage by SARS-CoV-2
复制标题
SARS-CoV-2 对动物血管紧张素转换酶 2 受体的广泛和差异化使用
DOI：
10.1128/jvi.00940-20
复制
发表时间：
2020-09-01
影响因子：
5.4
通讯作者：
Lin, Hanxin
中科院分区：
文献类型：
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作者：
Zhao, Xuesen;Chen, Danying;Lin, Hanxin
SARS-CoV-2使用人类ACE2作为宿主细胞进入的主要受体。ACE2与刺突蛋白相互作用介导的病毒进入在很大程度上决定了宿主范围，是种间传播的主要制约因素。我们检测了14个ACE2同源物的受体活性，发现野生型和突变型SARS-CoV-2在S蛋白中缺乏furin切割位点，可以利用来自多种动物物种的ACE2进入宿主细胞。这些结果对SARS-CoV-2的自然宿主、种间传播、动物模型和受体结合的分子基础具有重要意义。新冠肺炎大流行引发了前所未有的全球公共卫生和经济危机。尽管蝙蝠和穿山甲被认为是其天然宿主，但其致病因子SARS-CoV-2在人群中的起源和出现仍然是个谜。引人注目的是，与在蝙蝠和穿山甲中发现的SARS-CoV-2样冠状病毒（cov）不同，SARS-CoV-2在其刺突(S)糖蛋白中含有多碱基糠蛋白切割位点。SARS-CoV-2以人血管紧张素转换酶2 （ACE2）为受体感染细胞。S蛋白对受体的识别是冠状病毒宿主范围、组织趋向性和发病机制的主要决定因素。为了寻找SARS-CoV-2的潜在中间或扩增动物宿主，我们检测了来自14种哺乳动物的ACE2受体活性，发现来自多个物种的ACE2可以支持带有SARS-CoV-2野生型或furin切割位点缺陷S蛋白的假型慢病毒颗粒的感染进入。ACE2在人/恒河猴和大鼠/小鼠中分别表现出最高和最低的受体活性。在其他物种中，家兔和穿山甲的ACE2s与sars - cov - 2s蛋白S1亚基结合较强，有效地支持了假型病毒感染。这些发现对了解潜在的自然宿主、人畜共患传播、人-动物传播以及动物模型的使用具有重要意义。SARS-CoV-2使用人类ACE2作为宿主细胞进入的主要受体。ACE2与刺突蛋白相互作用介导的病毒进入在很大程度上决定了宿主范围，是种间传播的主要制约因素。我们检测了14个ACE2同源物的受体活性，发现野生型和突变型SARS-CoV-2在S蛋白中缺乏furin切割位点，可以利用来自多种动物物种的ACE2进入宿主细胞。这些结果对SARS-CoV-2的自然宿主、种间传播、动物模型和受体结合的分子基础具有重要意义。
SARS-CoV-2 uses human ACE2 as a primary receptor for host cell entry. Viral entry mediated by the interaction of ACE2 with spike protein largely determines host range and is the major constraint to interspecies transmission. We examined the receptor activity of 14 ACE2 orthologs and found that wild-type and mutant SARS-CoV-2 lacking the furin cleavage site in S protein could utilize ACE2 from a broad range of animal species to enter host cells. These results have important implications in the natural hosts, interspecies transmission, animal models, and molecular basis of receptor binding for SARS-CoV-2. ABSTRACT The COVID-19 pandemic has caused an unprecedented global public health and economic crisis. The origin and emergence of its causal agent, SARS-CoV-2, in the human population remains mysterious, although bat and pangolin were proposed to be the natural reservoirs. Strikingly, unlike the SARS-CoV-2-like coronaviruses (CoVs) identified in bats and pangolins, SARS-CoV-2 harbors a polybasic furin cleavage site in its spike (S) glycoprotein. SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as its receptor to infect cells. Receptor recognition by the S protein is the major determinant of host range, tissue tropism, and pathogenesis of coronaviruses. In an effort to search for the potential intermediate or amplifying animal hosts of SARS-CoV-2, we examined receptor activity of ACE2 from 14 mammal species and found that ACE2s from multiple species can support the infectious entry of lentiviral particles pseudotyped with the wild-type or furin cleavage site-deficient S protein of SARS-CoV-2. ACE2 of human/rhesus monkey and rat/mouse exhibited the highest and lowest receptor activities, respectively. Among the remaining species, ACE2s from rabbit and pangolin strongly bound to the S1 subunit of SARS-CoV-2 S protein and efficiently supported the pseudotyped virus infection. These findings have important implications for understanding potential natural reservoirs, zoonotic transmission, human-to-animal transmission, and use of animal models. IMPORTANCE SARS-CoV-2 uses human ACE2 as a primary receptor for host cell entry. Viral entry mediated by the interaction of ACE2 with spike protein largely determines host range and is the major constraint to interspecies transmission. We examined the receptor activity of 14 ACE2 orthologs and found that wild-type and mutant SARS-CoV-2 lacking the furin cleavage site in S protein could utilize ACE2 from a broad range of animal species to enter host cells. These results have important implications in the natural hosts, interspecies transmission, animal models, and molecular basis of receptor binding for SARS-CoV-2.