Latent infection with herpesviruses constitutively activates inflammasomes, while lytic replication suppresses their activation through distinct mechanisms. However, how Epstein–Barr virus (EBV) lytic replication inhibits the activation of inflammasomes remains unknown. Here, we reveal that the EBV immediate‐early protein BRLF1 inhibits inflammasome activation, and BRLF1 deficiency significantly increases the activation of inflammasomes and pyroptosis during early lytic lifecycle. BRLF1 interacts with RNA polymerase III subunits to suppress immunostimulatory small RNA transcription, RIG‐I inflammasome activation, and antiviral responses. Consequently, BRLF1‐deficient EBV primary infection induces robust T‐cell and NK cell activation and killing through IL‐1β and IL‐18. A BRLF1‐derived peptide that inhibits inflammasome activation is sufficient to suppress T‐cell and NK cell responses during BRLF1‐deficient EBV primary infection in lymphocytes. These results reveal a novel mechanism involved in the evasion of inflammasome activation and antiviral responses during EBV early lytic infection and provide a promising approach for the manipulation of inflammasomes against infection of oncogenic herpesviruses.

中文翻译：

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BRLF1 在早期 EBV 裂解生命周期中抑制 RNA Pol III 介导的 RIG-I 炎性体激活

疱疹病毒的潜伏感染组成性地激活炎性体，而裂解复制通过不同的机制抑制它们的激活。然而，爱泼斯坦-巴尔病毒 (EBV) 裂解复制如何抑制炎症小体的激活仍然未知。在这里，我们揭示了 EBV 即早期蛋白 BRLF1 抑制炎症小体的激活，而 BRLF1 缺乏在早期裂解生命周期中显着增加了炎症小体的激活和细胞焦亡。BRLF1 与 RNA 聚合酶 III 亚基相互作用，抑制免疫刺激性小 RNA 转录、RIG-I 炎性体激活和抗病毒反应。因此，BRLF1 缺陷型 EBV 原发感染通过 IL-1β 和 IL-18 诱导强大的 T 细胞和 NK 细胞活化和杀伤。抑制炎症小体激活的 BRLF1 衍生肽足以在 BRLF1 缺陷型 EBV 原发性感染淋巴细胞期间抑制 T 细胞和 NK 细胞反应。这些结果揭示了在 EBV 早期溶解感染期间逃避炎性体激活和抗病毒反应的新机制，并为控制炎性体以对抗致癌疱疹病毒感染提供了一种有前景的方法。