DNA感應在宿主細胞對抗DNA病毒的先天免疫反應中扮演重要角色。近幾年研究發現，STING是許多DNA感受器用來啟動下游先天免疫反應的共同中介者。在動物實驗中也證明了STING對於抵抗疱疹病毒感染扮演重要的角色。目前的研究指出人類疱疹病毒中的單純疱疹病毒一型、巨細胞病毒和卡波西氏肉瘤相關疱疹病毒的初次感染或潛伏感染，能夠透過cGAS或IFI16這兩個DNA感受器，活化STING調控的抗病毒途徑。但是對於同屬疱疹病毒的EB病毒在不同感染階段，能否以及如何引起STING途徑的活化仍不清楚。在本研究中，我們發現僅有在Rta誘發EB病毒再活化的情況下，才能夠引起STING途徑的活化，包括促進STING、TBK1和IRF3的磷酸化、IFN-β的表現以及STAT1的磷酸化。進一步藉由抑制STING的表現，我們確認了EB病毒再活化促進TBK1和IRF3磷酸化的現象主要是由STING所調控。我們也利用siRNA抑制cGAS和IFI16的蛋白質表現，發現cGAS對於EB病毒再活化所引起的STING途徑活化扮演重要角色。在利用藥物處理或Zta基因剔除阻止EB病毒DNA複製的情況下，Rta誘發EB病毒的再活化依然能促進STING途徑的活化，使我們排除病毒DNA複製、Zta和需要Zta啟動的基因在其中的重要性，並且推測Rta單獨啟動的病毒基因就能造成STING途徑的活化。最後，我們觀察到EB病毒再活化時，會增加細胞染色體DNA和粒線體DNA出現在細胞質液中，而這些細胞DNA可能是造成cGAS/STING途徑活化的原因。本研究除了幫助我們瞭解EB病毒再活化引起STING途徑活化的可能機制，也暗示cGAS/STING有可能參與EB病毒相關的疾病。

DNA sensing plays an important role in innate immunity against DNA viruses. Recently, stimulator of interferon genes (STING) was found to be a hub protein downstream of many DNA sensors, and its antiviral functions against herpesviruses have been proven in vivo. Primary or latent infection of herpes simplex virus-1, cytomegalovirus, and Kaposi’s sarcoma-associated herpesvirus can trigger a STING-mediated signaling pathway through DNA sensors including cGAS and IFI16. However, it remains unclear whether and how the pathway is triggered by another gammaherpesvirus: Epstein-Barr virus (EBV). In this study, we found that the STING-mediated signaling pathway can be activated only when EBV is reactivated into the lytic state. Through siRNA-mediated knockdown of specific DNA sensors, we found that cGAS, not IFI16, is important for the STING activation during EBV reactivation. Interestingly, EBV reactivation driven by a viral transactivator Rta can trigger the STING pathway even under treatment with a viral DNA polymerase inhibitor or knockout of a viral gene essential for viral DNA replication, indicating that viral DNA replication is not involved therein. On the other hand, we detected a significant increase of chromosomal DNA and mitochondrial DNA in cytosol upon EBV reactivation, suggesting that cellular DNA may be a stimulator of the cGAS/STING-mediated pathway therein. This study not only reveals a unique mechanism how EBV reactivation can trigger STING activation but also raises a possibility that activation of the cGAS/STING pathway may be linked to EBV-associated diseases.

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