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<p>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 virus infection.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月3日

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  • 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,
  • Ding Wei,
  • Xiaochun Chen,
  • Hao Tang,
  • Liu Yang,
  • Xu Yang,
  • Xiuxuan Sun,
  • Rui Yao,
  • Ye Zhao,
  • Weijun Qin,
  • Zhiwei Yang,
  • Liang Chen,
  • Huijie Bian,
  • Zhi-Nan Chen,
  • Ping Zhu

摘要

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 virus infection.