Wang Hongbo, Mou Zongjun, Yeo Yao Yu, Ge Qianyun, Liu Xiang, Narita Yohei, Li Zhixuan, Wang Chong, Li Wanyu, Zhao Katelyn Rs, Li Jenny, Bu Wei, Gewurz Benjamin, Cohen Jeffrey I, Teng Mingxiang, Dai Xinghong, Liu Xuefeng, Jiang Sizun, Zhao Bo
Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Nat Microbiol. 2025 Sep 26. doi: 10.1038/s41564-025-02126-0.
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.
