Human ACE2 Genetic Polymorphism Affecting SARS-CoV and SARS-CoV-2 Entry into Cells.
Human ACE2 Genetic Polymorphism Affecting SARS-CoV and SARS-CoV-2 Entry into Cells.
复制标题
DOI：
10.1128/spectrum.00870-22
复制
发表时间：
2022-08-31
影响因子：
3.7
通讯作者：
Takadaa, Ayato
中科院分区：
文献类型：
--
作者：
Hattori, Takanari;Saito, Takeshi;Okuya, Kosuke;Takahashi, Yuji;Miyamoto, Hiroko;Kajihara, Masahiro;Igarashi, Manabu;Takadaa, Ayato
严重急性呼吸综合征冠状病毒（SARS-CoV）和SARS-CoV-2具有单一的包膜糖蛋白（S蛋白），可与宿主细胞膜上的人血管紧张素转换酶2 （ACE2）结合。先前的突变扫描研究表明，人ACE2中与单核苷酸变异（snv）相对应的一些取代会影响sars - cov - 2s蛋白与受体结合域（RBD）的结合亲和力。然而，这些替换在实际病毒感染中的重要性尚不清楚。在本研究中，我们利用具有SARS-CoV和SARS-CoV-2的S蛋白假型的水疱性口炎印第安纳病毒（VSIV）研究了已报道的ACE2 SNV取代对SARS-CoV和SARS-CoV-2进入细胞的影响。转染表达每种SNV替换的ACE2质粒的HEK293T细胞感染假型vsiv，并与表达野生型ACE2的细胞比较，测定其相对感染性。我们发现SNV的一些替换对假型病毒的感染性有积极或消极的影响。特别是，H505R替代显著增强了假型vsiv的感染，包括那些在SARS-CoV-2变体的S蛋白RBD中发现替代的病毒。我们的研究结果表明，人类ACE2 snv可能潜在地影响细胞对SARS-CoV和SARS-CoV-2的敏感性。重要性：已知SARS-CoV和SARS-CoV-2可引起人类严重肺炎。这些冠状病毒的S蛋白与质膜上的ACE2分子结合，介导病毒进入细胞。S蛋白和ACE2之间的相互作用被认为是宿主对这些冠状病毒易感性的重要因素。虽然先前的研究表明，一些SNV在ACE2中的替换可能会影响与S蛋白的结合，但这些SNV的替换是否真的改变了SARS冠状病毒进入细胞的效率仍然是未知的。我们利用病毒表面含有S蛋白的假型vsv分析了ACE2 snv对SARS冠状病毒进入细胞的影响。我们发现SNV的一些替换对病毒的感染性有积极或消极的影响。我们的数据支持ACE2基因多态性可能潜在影响细胞对SARS冠状病毒的易感性的观点。
Severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 have a single envelope glycoprotein (S protein) that binds to human angiotensin-converting enzyme 2 (ACE2) on the host cell membrane. Previous mutational scanning studies have suggested that some substitutions corresponding to single nucleotide variants (SNVs) in human ACE2 affect the binding affinity to the receptor binding domain (RBD) of the SARS-CoV-2 S protein. However, the importance of these substitutions in actual virus infection is still unclear. In this study, we investigated the effects of the reported ACE2 SNV substitutions on the entry of SARS-CoV and SARS-CoV-2 into cells, using vesicular stomatitis Indiana virus (VSIV) pseudotyped with S proteins of these coronaviruses (CoVs). HEK293T cells transfected with plasmids expressing ACE2 having each SNV substitution were infected with the pseudotyped VSIVs and relative infectivities were determined compared to the cells expressing wild-type ACE2. We found that some of the SNV substitutions positively or negatively affected the infectivities of the pseudotyped viruses. Particularly, the H505R substitution significantly enhanced the infection with the pseudotyped VSIVs, including those having the substitutions found in the S protein RBD of SARS-CoV-2 variants of concern. Our findings suggest that human ACE2 SNVs may potentially affect cell susceptibilities to SARS-CoV and SARS-CoV-2. IMPORTANCE SARS-CoV and SARS-CoV-2 are known to cause severe pneumonia in humans. The S protein of these CoVs binds to the ACE2 molecule on the plasma membrane and mediates virus entry into cells. The interaction between the S protein and ACE2 is thought to be important for host susceptibility to these CoVs. Although previous studies suggested that some SNV substitutions in ACE2 might affect the binding to the S protein, it remains elusive whether these SNV substitutions actually alter the efficiency of the entry of SARS CoVs into cells. We analyzed the impact of the ACE2 SNVs on the cellular entry of SARS CoVs using pseudotyped VSIVs having the S protein on the viral surface. We found that some of the SNV substitutions positively or negatively affected the infectivities of the viruses. Our data support the notion that genetic polymorphisms of ACE2 may potentially influence cell susceptibilities to SARS CoVs.
登录
查看更多内容
DOI：
10.3390/v13010067
发表时间：
2021-01-06
期刊：
Viruses
影响因子：
--
作者：
Hashizume M;Gonzalez G;Ono C;Takashima A;Iwasaki M
通讯作者：
Iwasaki M
影响因子：
5.6
作者：
Huang SW;Wang SF
通讯作者：
Wang SF
影响因子：
11.4
作者：
Li, WH;Zhang, CS;Sui, JH;Kuhn, JH;Moore, MJ;Luo, SW;Wong, SK;Huang, IC;Xu, KM;Vasilieva, N;Murakami, A;He, YQ;Marasco, WA;Guan, Y;Choe, HY;Farzan, M
通讯作者：
Farzan, M
影响因子：
5.2
作者：
Benetti, Elisa;Tita, Rossella;Pinto, Anna Maria
通讯作者：
Pinto, Anna Maria
DOI：
10.1126/science.abc0870
发表时间：
2020-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chan KK;Dorosky D;Sharma P;Abbasi SA;Dye JM;Kranz DM;Herbert AS;Procko E
通讯作者：
Procko E