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Background <p>Since the emergence of COVID-19, SARS-CoV-2 Omicron variants have demonstrated increased human adaptation. Alveolar and recruited macrophages play a critical role in severe lung inflammation following SARS-CoV-2 infection, yet the mechanisms of viral entry into these immune cells remain incompletely understood.</p> Methods <p>Co-IP MS /MS was used to screen for potential SARS-CoV2 receptors in macrophages. Molecular docking, real-time interaction cytometry, and viral infection assays were employed to validate receptor identification. Single-cell RNA sequencing (scRNA-seq) of bronchoalveolar lavage fluid (BALF) from moderate and severe COVID-19 patients and healthy controls was analyzed to correlate receptor expression with disease severity. Transmission Electron Microscopy (TEM) was utilized to visualize viral particles and membrane fusion events.</p> Results <p>We identified CD98, a subunit of a heteromeric amino acid transporter, as a novel receptor for the SARS-CoV-2 spike protein. scRNA-seq analysis revealed elevated CD98 expression in pro-inflammatory M1-like macrophages, which were enriched in severe COVID-19 cases. Furthermore, TMPRSS11E, which is upregulated in M1 macrophages, facilitated spike protein cleavage and promoted membrane fusion, as confirmed by TEM. A functional interaction between TMPRSS11E and CD98 was also demonstrated.</p> Conclusion <p>The CD98/TMPRSS11E complex clusters on M1 macrophages, where CD98 serves both as a marker of inflammatory activation and a mediator of viral entry. Reduced spike cleavage efficiency of the Omicron variant correlates with its diminished entry into M1 macrophages. These findings reveal a CD98/TMPRSS11E-mediated entry mechanism that contributes to the tropism of SARS-CoV-2 for pro-inflammatory macrophages and may influence disease pathogenesis.</p>

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The macrophage entry mechanism of SARS-CoV-2 mediated by surface CD98/TMPRSS11E complex is associated with the cellular tropism toward proinflammatory M1 and pathogenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Ting Wang,
  • Yiwei Jiang,
  • Yumei Teng,
  • Jiahuang Li,
  • Chao Gao,
  • Ying Chi,
  • Lei Fang,
  • Nannan Wang,
  • Zhenfa Chen,
  • Wei Zhang,
  • Lunbiao Cui,
  • Jie Chao,
  • Shufeng Li,
  • Haibo Qiu

摘要

Background

Since the emergence of COVID-19, SARS-CoV-2 Omicron variants have demonstrated increased human adaptation. Alveolar and recruited macrophages play a critical role in severe lung inflammation following SARS-CoV-2 infection, yet the mechanisms of viral entry into these immune cells remain incompletely understood.

Methods

Co-IP MS /MS was used to screen for potential SARS-CoV2 receptors in macrophages. Molecular docking, real-time interaction cytometry, and viral infection assays were employed to validate receptor identification. Single-cell RNA sequencing (scRNA-seq) of bronchoalveolar lavage fluid (BALF) from moderate and severe COVID-19 patients and healthy controls was analyzed to correlate receptor expression with disease severity. Transmission Electron Microscopy (TEM) was utilized to visualize viral particles and membrane fusion events.

Results

We identified CD98, a subunit of a heteromeric amino acid transporter, as a novel receptor for the SARS-CoV-2 spike protein. scRNA-seq analysis revealed elevated CD98 expression in pro-inflammatory M1-like macrophages, which were enriched in severe COVID-19 cases. Furthermore, TMPRSS11E, which is upregulated in M1 macrophages, facilitated spike protein cleavage and promoted membrane fusion, as confirmed by TEM. A functional interaction between TMPRSS11E and CD98 was also demonstrated.

Conclusion

The CD98/TMPRSS11E complex clusters on M1 macrophages, where CD98 serves both as a marker of inflammatory activation and a mediator of viral entry. Reduced spike cleavage efficiency of the Omicron variant correlates with its diminished entry into M1 macrophages. These findings reveal a CD98/TMPRSS11E-mediated entry mechanism that contributes to the tropism of SARS-CoV-2 for pro-inflammatory macrophages and may influence disease pathogenesis.