慢性活动性EB病毒感染的遗传变异研究

Chronic active EB virus (CAEBV) infection is a severe lymphoproliferative disease that is caused by the persistent infection of EB virus (EBV) and is is more frequent in Asians. During its course, it may suddenly progress to hemophagocytic syndrome or tumors. Currently, there has been no effective curative approach and its mortality is high. At present, internationally there has been scarce systematic research of CAEBV, with only scattered case reports indicating that CAEBV exists the mutations of the genes STXBP2 and PRF1 related to the NK cellular function. Our previously study has revealed that CAEBV carried the susceptible gene mutations of the NK cellular functions and immunodeficiency syndrome using the Panel sequencing analyses of the initial 12 genes. Based on this, we proposed that it may be the important genetic basis of EBV infection that the immune genes resulted in the defects in the virus removal capacities. In this project, by text mining and indexing and collection of the databases on the known antiviral immune-related genes, a knowledge base will be established, and the whole exome sequencing will be conducted on 100 cases of Chinese CAEBV so as to further study the mutation spectrum, and the disease-causing genes will be screened through the knowledge base, in addition, the functional roles of the mutations will be explored through a series of assays . It is expected that in this project, the hereditary basis of CAEBV will be systematically interpreted internationally for the first time and gain a deeper understanding of the pathogenesis of CAEBV and other EBV-associated diseases and provide some new concepts to the clinical setup of therapeutic schemes.

慢性活动性EB病毒感染(CAEBV)是EB病毒(EBV)持续感染引发的恶性淋巴组织增殖性疾病，多分布于亚洲。病程中会急转为噬血细胞综合征或肿瘤，尚无有效治疗手段，致死率高。目前国际上缺少对CAEBV的系统性研究，仅有零散病例报道提示CAEBV存在NK细胞功能相关基因STXBP2、PRF1的突变。我们前期12个基因Panel测序分析发现CAEBV携带NK细胞功能及免疫缺陷综合征易感基因突变。我们据此提出免疫基因变异导致病毒清除能力缺陷可能是EBV感染的重要遗传基础。本项目拟通过文本挖掘和数据库检索收集已知抗病毒免疫相关基因建立知识库，并对100例中国CAEBV进行全外显子组测序进一步研究全景突变谱，知识库筛选致病基因，并通过实验探索突变的功能作用。本项目有望在国际上首次系统解析CAEBV的遗传基础，深入认识CAEBV 及EBV相关淋巴系统疾病的发病机制，为临床制定治疗新方案提供新观念。

EB病毒（Epstein-Barr virus, EBV）是最常见的人类疱疹病毒，90%以上成年人曾感染EBV。EBV持续感染T或NK细胞无法被清除，会导致EBV相关T/NK细胞淋巴组织增殖性疾病（EBV-T/NK-LPDs）。 EBV-T/NK-LPDs 中EBV持续感染的遗传基础尚不清楚。本研究系统地在大样本队列中（n=119）研究了EBV-T/NK-LPDs的先天突变和体细胞突变图谱，来明晰该类EBV感染疾病的遗传特征。为了探索EBV-T/NK-LPDs患者是否具有先天免疫缺陷，我们首先构建免疫基因知识库,包括了372个免疫相关基因。通过对97例EBV-T/NK-LPD患者进行全外显子组测序和对免疫相关基因进行基因水平突变负荷检测，我们新发现了EBV-T/NK-LPD的8个先天易感基因，包括KMT2D,IFIH1,UNC13D等。我们发现EB病毒感染的NK细胞常发生体细胞突变，解螺旋酶DDX3X（占比26.03%）、表观调控因子TET2, KMT2D, ARID1A等（占比35.62%）发生重现性体细胞突变。此外，EBV-T/NK-LPD病人发生RIG-I-like受体突变（DDX3X 和IFIH1突变）和表观遗传突变与未发生上述两类突变比较，预后更差。我们还发现RIG-I-like突变下调该通路活性并促使EB病毒编码基因LMP1等高表达。本项研究将有助于临床对EBV-T/NK-LPD的精准分层和新治疗策略的制定。