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

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

  • Nat Commun. 2024 Oct 9;15(1):8728. doi: 10.1038/s41467-024-53033-7.
Yuanchen Liu # 1,  Xiaoyu Zhao # 2 3,  Jialu Shi # 1,  Yajie Wang # 4,  Huan Liu # 1,  Ye-Fan Hu # 5,  Bingjie Hu 1,  Huiping Shuai 1,  Terrence Tsz-Tai Yuen 1 6,  Yue Chai 1,  Feifei Liu 1,  Hua-Rui Gong 7,  Jiayan Li 3,  Xun Wang 3,  Shujun Jiang 8,  Xiang Zhang 4,  Yanliang Zhang 8,  Xiangnan Li 9,  Lei Wang 1,  Madeline Hartnoll 1,  Tianrenzheng Zhu 1 6,  Yuxin Hou 1 6,  Xiner Huang 1 6,  Chaemin Yoon 1,  Yang Wang 1,  Yixin He 1,  Minmin Zhou 1,  Lianzhao Du 1,  Xiaojuan Zhang 1,  Wan-Mui Chan 1,  Lin-Lei Chen 1,  Jian-Piao Cai 1,  Shuofeng Yuan 1 6 10,  Jie Zhou 1 6,  Jian-Dong Huang 11 12,  Kwok-Yung Yuen 1 6 10 13 14 15,  Kelvin Kai-Wang To 1 6 10 14 15,  Jasper Fuk-Woo Chan 16 17 18 19 20 21,  Bao-Zhong Zhang 22,  Lei Sun 23,  Pengfei Wang 24,  Hin Chu 25 26 27 28
Affiliations

Affiliations

  • 1 State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
  • 2 Shanghai Sci-Tech Inno Center for Infection & Immunity, National Medical Center for Infectious Diseases, Huashan Hospital, Institute of Infection and Health, Fudan University, Shanghai, China.
  • 3 Shanghai Pudong Hospital, Fudan University Pudong Medical Center, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China.
  • 4 Shanghai Fifth People's Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 5 BayVax Biotech Limited, Hong Kong Science Park, Pak Shek Kok, New Territories, Hong Kong, China.
  • 6 Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China.
  • 7 Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 8 Department of Infectious Diseases, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 9 State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai, China.
  • 10 Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China.
  • 11 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
  • 12 Materials Innovation Institute for Life Sciences and Energy (MILES), HKU-SIRI, Shenzhen, China.
  • 13 Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Haikou, Hainan Province, China.
  • 14 Department of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China.
  • 15 Guangzhou Laboratory, Guangzhou, Guangdong Province, China.
  • 16 State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China. jfwchan@hku.hk.
  • 17 Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China. jfwchan@hku.hk.
  • 18 Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China. jfwchan@hku.hk.
  • 19 Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Haikou, Hainan Province, China. jfwchan@hku.hk.
  • 20 Department of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China. jfwchan@hku.hk.
  • 21 Guangzhou Laboratory, Guangzhou, Guangdong Province, China. jfwchan@hku.hk.
  • 22 Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. bz.zhang3@siat.ac.cn.
  • 23 Shanghai Fifth People's Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Institutes of Biomedical Sciences, Fudan University, Shanghai, China. llsun@fudan.edu.cn.
  • 24 Shanghai Pudong Hospital, Fudan University Pudong Medical Center, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China. pengfei_wang@fudan.edu.cn.
  • 25 State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China. hinchu@hku.hk.
  • 26 Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China. hinchu@hku.hk.
  • 27 Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China. hinchu@hku.hk.
  • 28 Materials Innovation Institute for Life Sciences and Energy (MILES), HKU-SIRI, Shenzhen, China. hinchu@hku.hk.
  • # Contributed equally.
PMID: 39379369 DOI: 10.1038/s41467-024-53033-7
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 ACE2H34, 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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