IFI16识别细胞核内病毒DNA，激活天然免疫和炎症小体。KSHV潜伏感染激活IFI16炎症小体，但裂解复制中IFI16信号尚无研究；更重要的是IFI16通路对KSHV感染和致病的作用并不清楚。我们的前期研究揭示IFI16抑制KSHV裂解复制、激活自噬反应和促进KSHV诱生肿瘤的生长，因此我们推测KSHV裂解复制激活急性IFI16炎症反应，抑制病毒的感染和复制，促使KSHV建立潜伏感染；而KSHV潜伏感染和低水平的裂解复制诱导持续的IFI16活化，上调自噬反应和促进KSHV诱生肿瘤的生长。本项目拟深入研究KSHV裂解感染对IFI16的调控作用，阐明急性IFI16炎症反应对KSHV裂解复制的抑制作用和机制、慢性IFI16炎症反应在KSHV致病和诱生肿瘤中的功能、对自噬反应的调控作用及其在KSHV感染和致病中的功能，揭示抗病毒作用的急性IFI16炎症反应和病毒诱生肿瘤的慢性IFI16炎症机制。

IFN-γ inducible protein 16 (IFI16) has been identified as a nuclear DNA sensor for exogenous and viral DNA to activate innate immune and inflammatory responses. Studies have shown that primary and latent KSHV infection activates IFI16- inflammasome, while IFI16 signal pathway during lytic replication remains unknown. Importantly, the role of IFI16 pathway in KSHV infection and pathogenesis has not been further documented. Our preliminary results revealed that IFI16 inhibits KSHV lytic replication, enhances autophagy and promotes KSHV-derived tumor growth, thus we hypothesize that KSHV lytic replication induces acute activation of IFI16-inflammasome, thereby inhibiting viral lytic infection and replication and establishing latent infection, whereas latent infection and a small portion of KSHV lytic replication induce chronic IFI16 inflammatory response and autophagy to promote the occurrence and growth of tumor in vivo. This project is planning to study the activation of IFI16 pathway during KSHV lytic lifecycle (Aim 1), to elucidate how acute IFI16 inflammasome inhibits KSHV lytic replication and alters epigenetic state of viral genome (Aim 2), to charactorize how KSHV-activated IFI16 enhances autophagy (Aim 3) and to reveal how chronic IFI16 activation promotes KSHV-derived tumor formation through inflammatory response and autophagy (Aim 4). These results will define the activation, signal pathway and physiological role of IFI16 during KSHV infection and pathogenesis, and further shed light on antiviral acute IFI16-inflammasome and tumor-promoting chronic IFI16 inflammatory response.