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
ABSTRACT 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, E484...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-04-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00099-22 |
| _version_ | 1818115946853695488 |
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| author | Wenlin Ren Xiaohui Ju Mingli Gong Jun Lan Yanying Yu Quanxin Long Devin J. Kenney Aoife K. O’Connell Yu Zhang Jin Zhong Guocai Zhong Florian Douam Xinquan Wang Ailong Huang Rong Zhang Qiang Ding |
| author_facet | Wenlin Ren Xiaohui Ju Mingli Gong Jun Lan Yanying Yu Quanxin Long Devin J. Kenney Aoife K. O’Connell Yu Zhang Jin Zhong Guocai Zhong Florian Douam Xinquan Wang Ailong Huang Rong Zhang Qiang Ding |
| author_sort | Wenlin Ren |
| collection | DOAJ |
| description | ABSTRACT 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 Δ145–146 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, Δ145–146, 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. |
| first_indexed | 2024-12-11T04:14:42Z |
| format | Article |
| id | doaj.art-938bbb2b9a754e049e0dce3905d0cf26 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-11T04:14:42Z |
| publishDate | 2022-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-938bbb2b9a754e049e0dce3905d0cf262022-12-22T01:21:17ZengAmerican Society for MicrobiologymBio2150-75112022-04-0113210.1128/mbio.00099-22Characterization of SARS-CoV-2 Variants B.1.617.1 (Kappa), B.1.617.2 (Delta), and B.1.618 by Cell Entry and Immune EvasionWenlin Ren0Xiaohui Ju1Mingli Gong2Jun Lan3Yanying Yu4Quanxin Long5Devin J. Kenney6Aoife K. O’Connell7Yu Zhang8Jin Zhong9Guocai Zhong10Florian Douam11Xinquan Wang12Ailong Huang13Rong Zhang14Qiang Ding15Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, ChinaCenter for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, ChinaCenter for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, ChinaSchool of Life Sciences, Tsinghua University, Beijing, ChinaCenter for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, ChinaKey Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, ChinaDepartment of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USADepartment of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USACenter for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, ChinaUnit of Viral Hepatitis, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, ChinaShenzhen Bay Laboratory, Shenzhen, ChinaDepartment of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USASchool of Life Sciences, Tsinghua University, Beijing, ChinaKey Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, ChinaKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Biosafety Level 3 Laboratory, Fudan University, Shanghai, ChinaCenter for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, ChinaABSTRACT 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 Δ145–146 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, Δ145–146, 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.https://journals.asm.org/doi/10.1128/mbio.00099-22COVID-19SARS-CoV-2Delta variantKappa variantB.1.618ACE2 decoy receptor |
| spellingShingle | Wenlin Ren Xiaohui Ju Mingli Gong Jun Lan Yanying Yu Quanxin Long Devin J. Kenney Aoife K. O’Connell Yu Zhang Jin Zhong Guocai Zhong Florian Douam Xinquan Wang Ailong Huang Rong Zhang Qiang Ding 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 mBio COVID-19 SARS-CoV-2 Delta variant Kappa variant B.1.618 ACE2 decoy receptor |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | COVID-19 SARS-CoV-2 Delta variant Kappa variant B.1.618 ACE2 decoy receptor |
| url | https://journals.asm.org/doi/10.1128/mbio.00099-22 |
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