"Characterization of SARS-CoV-2 Variants B.1.617.1 (Kappa), B.1.617.2 (Delta), and B.1.618 by Cell Entry and Immune Evasion"

作者全名："Ren, Wenlin; Ju, Xiaohui; Gong, Mingli; Lan, Jun; Yu, Yanying; Long, Quanxin; Kenney, Devin J.; O'Connell, Aoife K.; Zhang, Yu; Zhong, Jin; Zhong, Guocai; Douam, Florian; Wang, Xinquan; Huang, Ailong; Zhang, Rong; Ding, Qiang"

作者地址："[Ren, Wenlin; Ju, Xiaohui; Gong, Mingli; Yu, Yanying; Zhang, Yu; Ding, Qiang] Tsinghua Univ, Ctr Infect Dis Res, Sch Med, Beijing, Peoples R China; [Lan, Jun; Wang, Xinquan] Tsinghua Univ, Sch Life Sci, Beijing, Peoples R China; [Long, Quanxin; Huang, Ailong] Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Minist Educ, Chongqing, Peoples R China; [Kenney, Devin J.; O'Connell, Aoife K.; Douam, Florian] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA; [Kenney, Devin J.; O'Connell, Aoife K.; Douam, Florian] Boston Univ, Natl Emerging Infect Dis Labs, Boston, MA 02215 USA; [Zhong, Jin] Chinese Acad Sci, Inst Pasteur Shanghai, Unit Viral Hepatitis, CAS Key Lab Mol Virol & Immunol, Shanghai, Peoples R China; [Zhong, Guocai] Shenzhen Bay Lab, Shenzhen, Peoples R China; [Zhong, Guocai] Peking Univ, Sch Chem Biol & Biotechnol, Shenzhen Grad Sch, Shenzhen, Peoples R China; [Zhang, Rong] Fudan Univ, Shanghai Med Coll, Sch Basic Med Sci, Key Lab Med Mol Virol MOE NHC CAMS,Biosafety Leve, Shanghai, Peoples R China"

通信作者："Ding, Q (通讯作者)，Tsinghua Univ, Ctr Infect Dis Res, Sch Med, Beijing, Peoples R China."

来源：MBIO

ESI学科分类：MICROBIOLOGY

WOS号：WOS:000788061200053

JCR分区：Q1

影响因子：6.4

年份：2022

卷号：13

期号：2

开始页：　

结束页：　

文献类型：Article

关键词：COVID-19; SARS-CoV-2; Delta variant; Kappa variant; B; 1; 618; ACE2 decoy receptor

摘要："SARS-CoV-2, the causative agent of pandemic COVID-19, is rapidly evolving to be more transmissible and to exhibit evasive immune properties, compromising neutralization by antibodies from vaccinated individuals or convalescent-phase sera. Recently, SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta), and B.1.618 with mutations within the spike proteins were identified in India. Recently, highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants B.1.617.1 (Kappa), B.1.617.2 (Delta), and B.1.618 with mutations within the spike proteins were identified in India. The spike protein of Kappa contains the four mutations E154K, L452R, E484Q, and P681R, and Delta contains L452R, T478K, and P681R, while B.1.618 spike harbors mutations Delta 145-146 and E484K. However, it remains unknown whether these variants have alterations in their entry efficiency, host tropism, and sensitivity to neutralizing antibodies as well as entry inhibitors. In this study, we found that Kappa, Delta, or B.1.618 spike uses human angiotensin-converting enzyme 2 (ACE2) with no or slightly increased efficiency, while it gains a significantly increased binding affinity with mouse, marmoset, and koala ACE2 orthologs, which exhibit limited binding with wild-type (WT) spike. Furthermore, the P681R mutation leads to enhanced spike cleavage, which could facilitate viral entry. In addition, Kappa, Delta, and B.1.618 exhibit a reduced sensitivity to neutralization by convalescent-phase sera due to the mutation E484Q, T478K, Delta 145-146, or E484K, but remain sensitive to entry inhibitors such as ACE2-Ig decoy receptor. Collectively, our study revealed that enhanced human and mouse ACE2 receptor engagement, increased spike cleavage, and reduced sensitivity to neutralization antibodies of Kappa, Delta and B.1.618 may contribute to the rapid spread of these variants. Furthermore, our results also highlight that ACE2-Ig could be developed as a broad-spectrum antiviral strategy against SARS-CoV-2 variants. IMPORTANCE SARS-CoV-2, the causative agent of pandemic COVID-19, is rapidly evolving to be more transmissible and to exhibit evasive immune properties, compromising neutralization by antibodies from vaccinated individuals or convalescent-phase sera. Recently, SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta), and B.1.618 with mutations within the spike proteins were identified in India. In this study, we examined cell entry efficiencies of Kappa, Delta, and B.1.618. In addition, the variants, especially the Delta variant, exhibited expanded capabilities to use mouse, marmoset, and koala ACE2 for entry. Convalescent sera from patients infected with nonvariants showed reduced neutralization titers among the Kappa, Delta, and B.1.618 variants. Furthermore, the variants remain sensitive to ACE2-Ig decoy receptor. Our study thus could facilitate understanding how variants have increased transmissibility and evasion of established immunity and also could highlight the use of an ACE2 decoy receptor as a broad-spectrum antiviral strategy against SARS-CoV-2 variants."

基金机构："National Natural Science Foundation of China [32070153]; Tsinghua University Spring Breeze Fund [2021Z99CFY030]; Beijing Municipal Natural Science Foundation [M21001]; Advanced Customer Cultivation Project of Wuhan National Biosafety Laboratory, Chinese Academy of Sciences [2021ACCP-MS03]; Start-up Foundation of Tsinghua University [53332101319]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (32070153), Tsinghua University Spring Breeze Fund (2021Z99CFY030), Beijing Municipal Natural Science Foundation (M21001), Advanced Customer Cultivation Project of Wuhan National Biosafety Laboratory, Chinese Academy of Sciences (2021ACCP-MS03), and the Start-up Foundation of Tsinghua University (53332101319)."