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<p>Epstein–Barr virus (EBV) infects B and epithelial cells, causing various lymphomas and epithelial malignancies. Although cell-free infection of epithelial cells is inefficient, direct B–epithelial cell contact infection is highly efficient and probably the dominant route. To identify mechanisms of contact-mediated infection, we implemented a genome-wide CRISPR screen and uncovered desmocollin 2 (DSC2) as an EBV epithelial receptor and DSC3 as a co-factor for infection. <i>DSC2</i> and <i>DSC3</i> double knockout significantly inhibited both cell-free and cell–cell contact EBV infection of normal oral keratinocytes, while their overexpression permitted infection in receptor-negative cells. Antibodies to DSC2 blocked infection across normal oral keratinocytes, primary oral keratinocytes, and head and neck epithelial organoids. Combining DSC2 and DSC3 antibodies efficiently blocked cell–cell contact infection. Mechanistically, DSC2 interacted with the EBV gH/gL glycoprotein and facilitated epithelial fusion. Notably, EphA2 overexpression failed to restore infection in <i>DSC2</i>/<i>3</i>-deficient cells, indicating its dependence on DSC2/3. Our findings establish DSC2 as a principal EBV entry receptor and target for vaccine and therapeutic development.</p>

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Epstein–Barr virus exploits desmocollin 2 as the principal epithelial cell entry receptor

  • 期刊论文

  • 发表日期：

    2025年9月26日

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  • Hongbo Wang,
  • Zongjun Mou,
  • Yao Yu Yeo,
  • Qianyun Ge,
  • Xiang Liu,
  • Yohei Narita,
  • Zhixuan Li,
  • Chong Wang,
  • Wanyu Li,
  • Katelyn RS Zhao,
  • Jenny Li,
  • Wei Bu,
  • Benjamin Gewurz,
  • Jeffrey I. Cohen,
  • Mingxiang Teng,
  • Xinghong Dai,
  • Xuefeng Liu,
  • Sizun Jiang,
  • Bo Zhao

摘要

Epstein–Barr virus (EBV) infects B and epithelial cells, causing various lymphomas and epithelial malignancies. Although cell-free infection of epithelial cells is inefficient, direct B–epithelial cell contact infection is highly efficient and probably the dominant route. To identify mechanisms of contact-mediated infection, we implemented a genome-wide CRISPR screen and uncovered desmocollin 2 (DSC2) as an EBV epithelial receptor and DSC3 as a co-factor for infection. DSC2 and DSC3 double knockout significantly inhibited both cell-free and cell–cell contact EBV infection of normal oral keratinocytes, while their overexpression permitted infection in receptor-negative cells. Antibodies to DSC2 blocked infection across normal oral keratinocytes, primary oral keratinocytes, and head and neck epithelial organoids. Combining DSC2 and DSC3 antibodies efficiently blocked cell–cell contact infection. Mechanistically, DSC2 interacted with the EBV gH/gL glycoprotein and facilitated epithelial fusion. Notably, EphA2 overexpression failed to restore infection in DSC2/3-deficient cells, indicating its dependence on DSC2/3. Our findings establish DSC2 as a principal EBV entry receptor and target for vaccine and therapeutic development.