Epstein-Barr virus (EBV) is an oncogenic virus that infects more than 90% of the world's population ¹ . EBV predominantly infects human B cells and epithelial cells, which is initiated by fusion of the viral envelope with a host cellular membrane ² . The mechanism of EBV entry into B cells has been well characterized ³ . However, the mechanism for epithelial cell entry remains elusive. Here, we show that the integrins αvβ5, αvβ6 and αvβ8 do not function as entry and fusion receptors for epithelial cells, whereas Ephrin receptor tyrosine kinase A2 (EphA2) functions well for both. EphA2 overexpression significantly increased EBV infection of HEK293 cells. Using a virus-free cell-cell fusion assay, we found that EphA2 dramatically promoted EBV but not herpes simplex virus (HSV) fusion with HEK293 cells. EphA2 silencing using small hairpin RNA (shRNA) or knockout by CRISPR-Cas9 blocked fusion with epithelial cells. This inhibitory effect was rescued by the expression of EphA2. Antibody against EphA2 blocked epithelial cell infection. Using label-free surface plasmon resonance binding studies, we confirmed that EphA2 but not EphA4 specifically bound to EBV gHgL and this interaction is through the EphA2 extracellular domain (ECD). The discovery of EphA2 as an EBV epithelial cell receptor has important implications for EBV pathogenesis and may uncover new potential targets that can be used for the development of novel intervention strategies.

中文翻译：

---

Ephrin受体A2是Epstein-Barr病毒的功能性进入受体。

爱泼斯坦-巴尔病毒（EBV）是一种致癌病毒，感染了全球90％以上的人口¹。EBV主要感染人B细胞和上皮细胞，这是通过病毒包膜与宿主细胞膜²融合而引发的。EBV进入B细胞的机制已得到很好的表征³。然而，上皮细胞进入的机制仍然难以捉摸。在这里，我们显示出整联蛋白αvβ5，αvβ6和αvβ8不能作为上皮细胞的进入和融合受体，而Ephrin受体酪氨酸激酶A2（EphA2）的功能很好。EphA2过表达显着增加了HEK293细胞的EBV感染。使用无病毒的细胞-细胞融合测定法，我们发现EphA2显着促进EBV，但不促进单纯疱疹病毒（HSV）与HEK293细胞融合。使用小发夹RNA（shRNA）沉默EphA2或CRISPR-Cas9敲除EphA2可阻止与上皮细胞融合。该抑制作用通过EphA2的表达得以挽救。针对EphA2的抗体可阻止上皮细胞感染。使用无标记的表面等离振子共振结合研究，我们确认EphA2但不是EphA4特异性结合EBV gHgL，并且这种相互作用是通过EphA2细胞外结构域（ECD）进行的。EphA2作为EBV上皮细胞受体的发现对EBV发病机理具有重要意义，并可能发现新的潜在靶点，这些靶点可用于开发新的干预策略。