A non-spike nucleocapsid R204P mutation in SARS-CoV-2 Omicron XEC enhances inflammation and pathogenicity

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 investigate virological features of the XEC variant. Epidemic dynamics modeling suggests that spike substitutions in XEC mainly contribute to its increased viral fitness. Additionally, four licensed antivirals are effective against XEC. Although the fusogenicity of XEC spike is comparable to that of the JN.1 spike, the intrinsic pathogenicity of XEC in male hamsters is significantly higher than that of JN.1. Notably, we find that the nucleocapsid R204P mutation of XEC enhances 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.

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Journal
Nature Communications
Published
2025-12-14
DOI
https://doi.org/10.1038/s41467-025-67455-4
Citations
1
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
1.40

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article

A non-spike nucleocapsid R204P mutation in SARS-CoV-2 Omicron XEC enhances inflammation and pathogenicity

Wilaiporn Saikruang, Terumasa Ikeda, Naoko Yasuhara, Ryo Shimizu et al.
1 citations
Nature Communications
SARS-CoV-2 and COVID-19 Research
1.40
article

A non-spike nucleocapsid R204P mutation in SARS-CoV-2 Omicron XEC enhances inflammation and pathogenicity

Wilaiporn Saikruang, Terumasa Ikeda, Naoko Yasuhara, Ryo Shimizu, Shusuke Kawakubo, Hayato Ito, Arnon Plianchaisuk, Kaoru Usui, Keita Matsuno, Rina Hashimoto, Mika Chiba, Kanako Kimura, Kei Sato, Ayaka Sakamoto, Mako Toyoda, Akifumi Takaori‐Kondo, Ziyi Guo, Shuhei Tsujino, Hiroyuki Asakura, Hesham Nasser, Mami Nagashima, Akatsuki Saito, Yoshitaka Nakata, Yukio Watanabe, Masumi Tsuda, Yukari Nakajima, Alfredo A. Hinay, Kyoko Yasuda, Saori Suzuki, Keita Mizuma, Yoshitaka Oda, Yuma Ohari, Hirofumi Sawa, Spyros Lytras, Takasuke Fukuhara, Chihiro Motozono, Mai Suganami, Kazuo Takayama, Taha Y. Taha, Lin Pan, Miki Kawano, Tomokazu Tamura, Lei Wang, Naganori Nao, So Nakagawa, Naoko Misawa, Shinya Tanaka, Shigeru Fujita, Luca Nishimura, Jumpei Ito, Jingshu Li, Kenji Shishido, Tateki Suzuki, Kotaro Shirakawa, Mélanie Ott, Takamasa Ueno, Sayaka Deguchi, Ryoko Kawabata, Michael Jonathan, Rigel Suzuki, Takao Hashiguchi, Hiroki Futatsusako, Chen Luo, Jarel M. Tolentino, Isao Yoshida, Julia Rosecrans, Kumiko Yoshimatsu, Kazuhisa Yoshimura, Yusuke Kosugi, Kenji Sadamasu, Hisano Yajima, Yume Mimura, Anon Kosaka, Takashi Irie, Keiya Uriu, Begum MST Monira
article en
1 citations

Abstract

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 investigate virological features of the XEC variant. Epidemic dynamics modeling suggests that spike substitutions in XEC mainly contribute to its increased viral fitness. Additionally, four licensed antivirals are effective against XEC. Although the fusogenicity of XEC spike is comparable to that of the JN.1 spike, the intrinsic pathogenicity of XEC in male hamsters is significantly higher than that of JN.1. Notably, we find that the nucleocapsid R204P mutation of XEC enhances 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.

Nature CommunicationsVol. 17(1)
Hokkaido University of Science (JP), Hiroshima University (JP), University of Miyazaki (JP), Tokai University (JP), Gladstone Institutes (US), Kyushu University (JP), Hokkaido University of Education (JP), Tokyo Medical University (JP), University of California, San Francisco (US), Sapporo University (JP), Hokkaido University (JP), Hokkaido Pharmaceutical University (JP), Kyoto University (JP), Japan Agency for Medical Research and Development (JP), National Institute of Infectious Diseases (JP), Tokyo Metropolitan Institute of Public Health (JP), Chan Zuckerberg Initiative (United States) (US), Duke-NUS Medical School (SG), Murayama Medical Center (JP), MRC University of Glasgow Centre for Virus Research (GB), Kyoto University Hospital (JP), The University of Tokyo (JP), Hokkai Gakuen University (JP), Kumamoto University (JP), The University of Osaka (JP)
Akiyama Life Science Foundation, Uehara Memorial Foundation, Japan Agency for Medical Research and Development, Roddenberry Foundation, James B. Pendleton Charitable Trust, Tokyo Biochemical Research Foundation, Hirose Foundation, University of Tokyo, Hokkaido University, National Institutes of Health, Japan Society for the Promotion of Science, Institute of Medical Science, University of Tokyo, Core Research for Evolutional Science and Technology, Precursory Research for Embryonic Science and Technology
Openalex Percentile: Top 14%
SARS-CoV-2 and COVID-19 Research
1.40
DOIOpen Access PDFOpenAlex
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