EB病毒感染鼻咽上皮细胞降解BST2/Tetherin逃逸天然免疫的机制

BST2, also known as Tetherin, is the interferon-induced cellular membrane factor responsible for the suppression of a variety of enveloped viruses through the restriction of virions release from the host cell surface. Epstein-Barr virus (EBV), has been implicated as an etiological factor in nasopharyngeal carcinoma (NPC), a malignant epithelial cancer occurred frequently in South China and Southeast Asia. However, the mechanism for EBV infection and its evasion of innate immune remained to be elucidated. We found that the mRNA of BST2 was induced by EBV infection through the transcriptome analysis of nasopharyngeal epithelial cells with or without EBV infection as well as the NPC tumor tissues and normal nasopharyngeal tissues. Exogenous expression of BST2 inhibited the release of EBV virion, while downregulation of BST-2 promoted virions release and EBV infection. The mRNA level of BST2 was induced by EBV infection. However, the protein level of BST2 was downregulated in EBV infection of immortalized nasopharyngeal epithelial cells (NPEC1-Bmi1 and NPEC2-Bmi1). BST2 protein expression was higher in the non-cancerous samples (NPN) and the counterpart non-cancerous tissues compared with the NPC tumor tissues. Taken together, these results indicated that BST2 suppressed the virus release. In addition, EBV may evade the innate immune through the degradation of BST2 in nasopharyngeal epithelial cells. In this study, we plan to identify the EBV encoding genes responsible for the degradation of BST2 to elucidate the mechanism for the evasion of innate immune by EBV. This study will lead to significant enhancements to our understanding how EBV evades the innate immune in its host nasopharyngeal epithelial cells. In addition, the results will provide molecular evidence to explore novel antiviral interventions therapeutic target for NPC.

BST2，也称Tetherin，是I型干扰素诱导的抗病毒天然免疫分子，限制多种囊膜病毒释放。EB病毒感染与鼻咽癌相关，病毒逃逸鼻咽上皮细胞天然免疫及其潜伏感染机制尚不清楚。通过建立EB病毒高效感染鼻咽上皮细胞模型、分析病毒感染前后表达谱芯片和鼻咽癌转录组数据，发现EB病毒感染诱导BST2 mRNA表达，敲低BST2促进病毒感染及释放，过表达BST2抑制病毒分泌。EB病毒感染后，BST2 mRNA显著上调，蛋白水平却降低；在EB病毒阳性的鼻咽癌组织中，BST2表达显著低于正常上皮组织。提示：BST2限制EB病毒释放，而病毒促进BST2蛋白降解，继而逃逸BST2分子限制。本项目采用免疫共沉淀和质谱分析等技术，筛选、鉴定降解BST2的关键病毒蛋白，阐明EB病毒拮抗BST2逃逸天然免疫的机制。相关成果将填补EB病毒逃逸鼻咽上皮细胞天然免疫研究空白，为EB病毒清除和鼻咽癌治疗提供新的思路和靶点。

BST2，是I型干扰素诱导的抗病毒天然免疫分子，限制多种囊膜病毒释放。EB病毒感染与鼻咽癌相关，但病毒逃逸鼻咽上皮细胞天然免疫及其潜伏感染机制尚不清楚。通过建立EB病毒高效感染鼻咽上皮细胞模型、分析病毒感染前后表达谱芯片和鼻咽癌转录组数据，发现EB病毒感染诱导BST2 mRNA表达，敲低BST2促进病毒感染及释放，过表达BST2抑制病毒分泌。EB病毒感染后，BST2 mRNA显著上调，蛋白水平却降低；在EB病毒阳性的鼻咽癌组织中，BST2表达显著低于正常上皮组织。提示：BST2限制EB病毒释放。而病毒促进BST2蛋白降解，继而逃逸BST2分子限制机制并不清楚，为了进一步阐明EB病毒促进BST2降解机制，我们过表达近20种病毒编码相关基因，发现EB病毒裂解复制基因ZTA促进BST2蛋白降解；已有文献表明，BTRC促进BST2降解，参与HIV天然免疫逃逸，我们进一步研究发现，ZTA通过上调BTRC表达促进BST2蛋白降解。这些研究结果，阐明了EB病毒裂解复制基因ZTA促进BST2降解逃逸上皮细胞天然免疫的机制。相关研究成果为EB病毒清除和鼻咽癌治疗提供新的思路和靶点。