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The interaction of Epstein-Barr virus encoded transcription factor EBNA2 with multiple sclerosis risk loci is dependent on the risk genotype
EBioMedicine ( IF 11.1 ) Pub Date : 2021-09-03 , DOI: 10.1016/j.ebiom.2021.103572
Jeremy Thomas Keane 1 , Ali Afrasiabi 2 , Stephen Donald Schibeci 1 , Sanjay Swaminathan 3 , Grant Peter Parnell 1 , David Richmond Booth 1
Affiliation  

Background

Epstein-Barr virus (EBV) infection may be necessary for the development of Multiple sclerosis (MS). Earlier we had identified six MS risk loci that are co-located with binding sites for the EBV transcription factor Epstein-Barr Nuclear Antigen 2 (EBNA2) in EBV-infected B cells (lymphoblastoid cell lines – LCLs).

Methods

We used an allele-specific chromatin immunoprecipitation PCR assay to assess EBNA2 allelic preference. We treated LCLs with a peptide inhibitor of EBNA2 (EBNA2-TAT), reasoning that inhibiting EBNA2 function would alter gene expression at these loci if it was mediated by EBNA2.

Findings

We found that EBNA2 binding was dependent on the risk allele for five of these six MS risk loci (p < 0·05). Treatment with EBNA2-TAT significantly altered the expression of TRAF3 (p < 0·05), CD40 (p < 0·001), CLECL1 (p <0·0001), TNFAIP8 (p < 0·001) and TNFRSF1A (p < 0·001).

Interpretation

These data suggest that EBNA2 can enhance or reduce expression of the gene depending on the risk allele, likely promoting EBV infection. This is consistent with the concept that these MS risk loci affect MS risk through altering the response to EBNA2. Together with the extensive data indicating a pathogenic role for EBV in MS, this study supports targeting EBV and EBNA2 to reduce their effect on MS pathogenesis.

Funding

Funding was provided by grants from MS Research Australia, National Health and Medical Research Council of Australia, Australian Government Research Training Program, Multiple Sclerosis International Federation, Trish Multiple Sclerosis Research Foundation.



中文翻译:

Epstein-Barr 病毒编码的转录因子 EBNA2 与多发性硬化症风险基因座的相互作用取决于风险基因型

背景

爱泼斯坦-巴尔病毒 (EBV) 感染可能是多发性硬化症 (MS) 发展所必需的。早些时候,我们已经确定了六个 MS 风险基因座,它们与 EBV 感染的 B 细胞(淋巴母细胞系 - LCL)中的 EBV 转录因子 Epstein-Barr 核抗原 2 (EBNA2) 的结合位点位于同一位置。

方法

我们使用等位基因特异性染色质免疫沉淀 PCR 测定来评估 EBNA2 等位基因偏好。我们用 EBNA2 的肽抑制剂 (EBNA2-TAT) 处理 LCL,理由是抑制 EBNA2 功能会改变这些基因座的基因表达,如果它是由 EBNA2 介导的。

发现

我们发现 EBNA2 结合依赖于这六个 MS 风险基因座中的五个的风险等位基因 ( p < 0·05)。EBNA2-TAT 治疗显着改变了 TRAF3 ( p < 0·05)、CD40 ( p < 0·001)、CLECL1 ( p <0·0001)、TNFAIP8 ( p < 0·001) 和 TNFRSF1A ( p < 0·001)。

解释

这些数据表明 EBNA2 可以根据风险等位基因增强或减少基因的表达,可能促进 EBV 感染。这与这些 MS 风险基因座通过改变对 EBNA2 的反应影响 MS 风险的概念是一致的。连同表明 EBV 在 MS 中的致病作用的大量数据,本研究支持靶向 EBV 和 EBNA2 以减少它们对 MS 发病机制的影响。

资金

资金由澳大利亚 MS 研究、澳大利亚国家健康和医学研究委员会、澳大利亚政府研究培训计划、多发性硬化症国际联合会、Trish 多发性硬化症研究基金会提供。

更新日期:2021-09-04
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