EBV感染通过多种机制逃逸免疫、调控炎症反应和诱导疾病，是多种疾病和肿瘤的主要病因之一；但EBV对炎症反应的调控作用仍有许多问题尚未解决，特别是潜伏感染转向裂解复制过程中炎症小体的活性变化和功能亟待阐明。我们已证明EBV裂解复制即早期基因BZLF1抑制TNFα分泌、抑制抗病毒炎症反应和终止旁分泌诱导的细胞衰老；最近我们发现另一个即早期基因BRLF1抑制炎症小体活性，进而抑制IL-18诱导的NK细胞活化，因此我们提出假说：EBV原代感染和早期裂解复制通过BRLF1抑制炎症小体活化，降低炎症小体依赖性炎症因子和外泌体分泌、逃逸炎症小体的抗病毒作用，促进EBV复制和持续感染。本项目将阐明EBV早期裂解复制通过BRLF1抑制炎症小体活化的机制和功能，揭示EBV裂解复制过程中炎症小体依赖性天然免疫功能抑制和逃逸机制，探讨激活炎症小体阻断EBV感染和复制的新策略，为EBV感染性疾病防治研究提供新思路。

Epstein-Barr virus (EBV) is one of the key causative factors of various severe diseases and malignant tumors. It employs multiple strategies to escape antiviral immunity, regulate inflammation and induce diseases. Although inflammatory responses are differentially regulated and play the critical role in EBV persistent infection and pathogenesis, however, many questions of inflammation during EBV infection remain unclear, especially the alteration and function of inflammasome during the switch from latency to lytic lifecycle remain to be explored. We have revealed that BZLF1 mediates the inhibition of pro-inflammatory responses and then promotes the optimal lytic replication and attenuates the transmission of paracrine senescence during lytic replication. By EBV ORFs expressing library screening, we have also identified that BRLF1 inhibits the activation of inflammasome and IL-18-induced NK cell activation. Thus we hypothesize that EBV early lytic lifecycle suppresses the activation of inflammasome through BRLF1, resulting in inhibition of inflammasome-mediated antiviral responses during EBV primary infection and reactivation from the latency. This project aims to reveal the inhibition of inflammasome by BRLF1 during early lytic EBV infection (Aim 1), to study the evasion of inflammasome-dependent innate immune responses during EBV lytic lifecycle (Aim 2), and to investigate the potentials of activation of inflammasome against EBV lytic infection (Aim 3). Our studies will clarify the evasion of inflammasome in EBV lytic infection and further explore a novel strategy for the treatment of EBV-related diseases by targeting inflammasome.