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<p>Epstein–Barr virus (EBV) can infect B cells and epithelial cells, and cause lymphomas and various epithelial malignancies. During epithelial cell infection, EBV employs a complex combination of viral glycoproteins and host receptors. However, the exact mechanism and whether a dominant receptor exists remain unclear. Here we identify desmocollin 2 (DSC2) as a dominant EBV entry receptor for epithelial cell infection using CRISPR–Cas9 screening. Knockout of <i>DSC2</i> reduced EBV infection in both nasopharyngeal and gastric epithelial cell lines, and infection was rescued when DSC2 expression was restored. Expression of human DSC2 in non-EBV-susceptible hamster cell lines enabled susceptibility to EBV. Furthermore, we found that DSC2 directly binds to EBV glycoprotein H/glycoprotein L through its extracellular domain, particularly the preEC–EC2 regions, which could be targeted by polyclonal antibodies, therefore blocking EBV infection in primary epithelial cells. DSC2 enabled virus entry independent of Ephrin receptor A2. These findings could aid development of currently unavailable animal models and support development of targeted therapies.</p>

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Desmocollin 2 is a dominant entry receptor for Epstein–Barr virus infection of epithelial cells

  • 期刊论文

  • 发表日期：

    2025年7月25日

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  • Hua Zhang,
  • Yu-Chun Li,
  • De Pang,
  • Chu Xie,
  • Ting Zhang,
  • Ying Li,
  • Yan Li,
  • Zi-Ying Jiang,
  • Guo-Long Bu,
  • Meng-Meng Liu,
  • Ying-Rou Chen,
  • Han-Xiao Fei,
  • Ruo-Bin Lin,
  • Pei-Huang Wu,
  • Wen-Ting Du,
  • Ge-Xin Zhao,
  • Yi-Ling Luo,
  • Ping Han,
  • Qian Zhong,
  • Cong Sun,
  • Mu-Sheng Zeng

摘要

Epstein–Barr virus (EBV) can infect B cells and epithelial cells, and cause lymphomas and various epithelial malignancies. During epithelial cell infection, EBV employs a complex combination of viral glycoproteins and host receptors. However, the exact mechanism and whether a dominant receptor exists remain unclear. Here we identify desmocollin 2 (DSC2) as a dominant EBV entry receptor for epithelial cell infection using CRISPR–Cas9 screening. Knockout of DSC2 reduced EBV infection in both nasopharyngeal and gastric epithelial cell lines, and infection was rescued when DSC2 expression was restored. Expression of human DSC2 in non-EBV-susceptible hamster cell lines enabled susceptibility to EBV. Furthermore, we found that DSC2 directly binds to EBV glycoprotein H/glycoprotein L through its extracellular domain, particularly the preEC–EC2 regions, which could be targeted by polyclonal antibodies, therefore blocking EBV infection in primary epithelial cells. DSC2 enabled virus entry independent of Ephrin receptor A2. These findings could aid development of currently unavailable animal models and support development of targeted therapies.