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.
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.
Nat Commun. 2024 Oct 9;15(1):8728. doi: 10.1038/s41467-024-53033-7.
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, 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.
与母株 BA.2.86 相比，SARS-CoV-2 JN.1 在刺突蛋白上有一个额外的 L455S 突变，它已经击败了所有早期变体，成为主要的流行变体。最近的研究调查了 SARS-CoV-2 JN.1 的免疫抗性，但推测还有其他因素促成了它的全球主导地位，直到今天这一点仍然难以捉摸。在这里，我们发现在分化的原代人鼻上皮细胞（hNECs）中，SARS-CoV-2 JN.1 的感染性比 BA.2.86 更高。从机制上讲，我们证明 SARS-CoV-2 JN.1 相对于 BA.2.86 的获得性感染性与 L455S 赋予的更高进入效率以及 hNECs 中更好的刺突裂解有关。结构上，与 BA.2.86 刺突相比，S455 改变了 JN.1 刺突蛋白与 ACE2 结合的模式，并且通过增加与相邻残基的氢键数量来改变 JN.1 刺突蛋白的内部结构。这些发现表明，单个突变（L455S）增强了 hNECs 中的病毒进入并增加了免疫逃逸，这有助于 SARS-CoV-2 JN.1 的强大传染性。我们进一步评估了 SARS-CoV-2 BA.2.86/JN.1 和 EG.5.1/HK.3 之间的体外和体内病毒学特征，并确定了这两个奥密克戎亚系的关键谱系特异性特征，有助于我们了解奥密克戎的抗原性、传染性和致病性。
