Tsujino Shuhei, Tsuda Masumi, Ito Jumpei, Deguchi Sayaka, Taha Taha Y, Nasser Hesham, Wang Lei, Rosecrans Julia, Suzuki Rigel, Suzuki Saori, Yoshimatsu Kumiko, Ott Melanie, Ikeda Terumasa, Takayama Kazuo, Sato Kei, Tanaka Shinya, Tamura Tomokazu, Fukuhara Takasuke
Department of Virology, Faculty of Medicine Sciences, Kyushu University, Fukuoka, Japan.
Department of Microbiology and Immunology, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
bioRxiv. 2025 May 30:2025.05.28.656516. doi: 10.1101/2025.05.28.656516.
The global circulation of SARS-CoV-2 in human populations has driven the emergence of Omicron subvariants, which have become highly diversified through recombination. In late 2024, SARS-CoV-2 Omicron XEC variant emerged from the recombination of two JN.1 progeny, KS.1.1 and KP.3.3, and became predominant worldwide. Here, we investigated virological features of the XEC variant. Epidemic dynamics modeling suggested that spike substitutions in XEC mainly contribute to its increased viral fitness. Additionally, four licensed antivirals were effective against XEC. Although the fusogenicity of XEC spike is comparable to that of the JN.1 spike, the intrinsic pathogenicity of XEC in hamsters was significantly higher than that of JN.1. Notably, we found that the nucleocapsid R204P mutation of XEC enhanced inflammation through NF-κB activation. Recent studies suggest that the evolutionary potential of spike protein is reaching its limit. Indeed, our findings highlight the critical role of non-spike mutations in the future evolution of SARS-CoV-2.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）在人群中的全球传播促使奥密克戎亚变体出现，这些亚变体通过重组变得高度多样化。2024年末，SARS-CoV-2奥密克戎XEC变体由两个JN.1子代KS.1.1和KP.3.3重组产生，并在全球范围内占据主导地位。在此，我们研究了XEC变体的病毒学特征。流行动力学模型表明，XEC中的刺突蛋白替换主要导致其病毒适应性增加。此外，四种已获许可的抗病毒药物对XEC有效。虽然XEC刺突蛋白的融合性与JN.1刺突蛋白相当，但XEC在仓鼠体内的内在致病性显著高于JN.1。值得注意的是，我们发现XEC的核衣壳R204P突变通过激活核因子κB（NF-κB）增强炎症反应。近期研究表明，刺突蛋白的进化潜力已接近极限。事实上，我们的研究结果凸显了非刺突突变在SARS-CoV-2未来进化中的关键作用。
