Lineage-specific pathogenicity, immune evasion, and virological features of SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3

SARS-CoV-2 JN.1 with an additional L455S mutation on spike when compared with its parental variant BA.2.86 has outcompeted all earlier variants to become the dominant circulating variant. Recent studies investigated the immune resistance of SARS-CoV-2 JN.1 but additional factors are speculated to contribute to its global dominance, which remain elusive until today. Here, we find that SARS-CoV-2 JN.1 has a higher infectivity than BA.2.86 in differentiated primary human nasal epithelial cells (hNECs). Mechanistically, we demonstrate that the gained infectivity of SARS-CoV-2 JN.1 over BA.2.86 associates with increased entry efficiency conferred by L455S and better spike cleavage in hNECs. Structurally, S455 altered the mode of binding of JN.1 spike protein to ACE2 when compared to BA.2.86 spike at ACE2<sup>H34</sup>, and modified the internal structure of JN.1 spike protein by increasing the number of hydrogen bonds with neighboring residues. These findings indicate that a single mutation (L455S) enhances virus entry in hNECs and increases immune evasiveness, which contribute to the robust transmissibility of SARS-CoV-2 JN.1. We further evaluate the in vitro and in vivo virological characteristics between SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3, and identify key lineage-specific features of the two Omicron sublineages that contribute to our understanding on Omicron antigenicity, transmissibility, and pathogenicity.

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Publication Details

Journal
Nature Communications
Published
2024-10-09
DOI
https://doi.org/10.1038/s41467-024-53033-7
Citations
44
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
17.12

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article

Lineage-specific pathogenicity, immune evasion, and virological features of SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3

Jie Zhou, Ye‐Fan Hu, Chaemin Yoon, Kelvin Kai‐Wang To et al.
44 citations
Nature Communications
SARS-CoV-2 and COVID-19 Research
17.12
article

Lineage-specific pathogenicity, immune evasion, and virological features of SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3

Jie Zhou, Ye‐Fan Hu, Chaemin Yoon, Kelvin Kai‐Wang To, Lei Sun, Yue Chai, Shuofeng Yuan, Lin‐Lei Chen, Tianrenzheng Zhu, Bingjie Hu, Huiping Shuai, Hin Chu, Jasper Fuk‐Woo Chan, Madeline Hartnoll, Minmin Zhou, Hua‐Rui Gong, Xiner Huang, Yuxin Hou, Jian‐Piao Cai, Wan-Mui Chan, Yuanchen Liu, Kwok‐Yung Yuen, Yanliang Zhang, Jialu Shi, Xiaoyu Zhao, Yang Wang, Xiang Zhang, Pengfei Wang, Wenxin Wang, Yixin He, Bao‐Zhong Zhang, Xiangnan Li, Huan Liu, Jiayan Li, Shujun Jiang, Terrence Tsz‐Tai Yuen, Jian‐Dong Huang, Lianzhao Du, Feifei Liu, Yajie Wang, Xun Wang, Xiaojuan Zhang
article en
44 citations

Abstract

SARS-CoV-2 JN.1 with an additional L455S mutation on spike when compared with its parental variant BA.2.86 has outcompeted all earlier variants to become the dominant circulating variant. Recent studies investigated the immune resistance of SARS-CoV-2 JN.1 but additional factors are speculated to contribute to its global dominance, which remain elusive until today. Here, we find that SARS-CoV-2 JN.1 has a higher infectivity than BA.2.86 in differentiated primary human nasal epithelial cells (hNECs). Mechanistically, we demonstrate that the gained infectivity of SARS-CoV-2 JN.1 over BA.2.86 associates with increased entry efficiency conferred by L455S and better spike cleavage in hNECs. Structurally, S455 altered the mode of binding of JN.1 spike protein to ACE2 when compared to BA.2.86 spike at ACE2<sup>H34</sup>, and modified the internal structure of JN.1 spike protein by increasing the number of hydrogen bonds with neighboring residues. These findings indicate that a single mutation (L455S) enhances virus entry in hNECs and increases immune evasiveness, which contribute to the robust transmissibility of SARS-CoV-2 JN.1. We further evaluate the in vitro and in vivo virological characteristics between SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3, and identify key lineage-specific features of the two Omicron sublineages that contribute to our understanding on Omicron antigenicity, transmissibility, and pathogenicity.

Nature CommunicationsVol. 15(1)
Nanjing University of Chinese Medicine (CN), Fudan University (CN), Queen Mary Hospital (CN), Hong Kong Science and Technology Parks Corporation (HK), Guangzhou Experimental Station (CN), Key Laboratory of Guangdong Province (CN), Pudong Medical Center (CN), University of Hong Kong - Shenzhen Hospital (CN), HKU-Pasteur Research Pole (HK), Shenzhen Institutes of Advanced Technology (CN), Obstetrics and Gynecology Hospital of Fudan University (CN), Institut de Recherche et d’Innovation (FR), Huashan Hospital (CN), State Key Laboratory of Genetic Engineering, Hainan Medical University (CN), University of Hong Kong (HK)
National Natural Science Foundation of China, Fudan University, Innovation and Technology Commission, Food and Health Bureau, Health and Medical Research Fund, Young Scientists Fund, Sanming Project of Medicine in Shenzhen, Shanghai Medical College, Fudan University
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