Inducible CD147 up-regulation boosts extended SARS-CoV-2 infection triggering severe COVID-19 independent of ACE2

作者：Ke Wang, Peng Lin, Ruo Chen, Qiang Huang, Yizhen Zhao, Lei Zhang, Yongxiang Zhao, Liping Zhong, Ke Xu, Linlin Bao, Youchun Wang, Chuan Qin, Guizhen Wu, Hai Zhang, Jiejie Geng, Zheng Zhang, Wei Ding, Xiaochun Chen, Hao Tang, Liu Yang, Xu Yang, Xiuxuan Sun, Rui Yao, Ye Zhao, Weijun Qin, Zhiwei Yang, Liang Chen, Bian Huijie, Zhi‐Nan Chen, Ping Zhu · 发表于：Signal Transduction and Targeted Therapy · 年份：2026 · DOI：10.1038/s41392-025-02551-x · 被引用次数：1 · 研究领域：Signaling Pathways in Disease、Galectins and Cancer Biology、Calcium signaling and nucleotide metabolism

The high mortality caused by severe COVID-19 poses great challenges to the public health. However, the underlying pathogenesis of severe cases remains unclear. Here, we find that SARS-CoV-2 infection boosts CD147 inducible up-regulation in the lung tissues of virus-infected rhesus macaques coupled with down-regulated membrane-bound ACE2, which conduces to extended virus infection and severe pathological lesions. Specifically, SARS-CoV-2 infection enhances the expression of transcriptional factor aryl hydrocarbon receptor and facilitates its nucleus translocation, which causes CD147 gene transcription and its up-regulation in protein level, thereby leading to virus susceptibility of the hosts and extended virus infection. Meanwhile, SARS-CoV-2 infection triggers immune imbalance of lung tissues by promoting cell death of CD4 + T cells and B cells and mediating abnormal cell-cell communications, especially for M2 macrophages. Meplazumab, a humanized anti-CD147 antibody, effectively inhibits virus entry and cytokine level, and restores immune balance in the lung tissues of virus-infected rhesus macaque model. Importantly, we further present the cryo-EM structure of CD147-spike complex, and identify five pairs of functional residues for their interaction, which could be interrupted by Meplazumab via steric hindrance effect. Our findings provide direct evidence for CD147-SARS-CoV-2 spike interaction and uncover the pathogenesis of severe COVID-19 caused by CD147-mediated extended ...