IFI16在卡波氏肉瘤相关疱疹病毒感染和致病中的作用和机制

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.

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。

IFI16识别细胞核内病毒DNA，激活天然免疫和炎症小体。KSHV原代感染和潜伏感染激活IFI16免疫炎症反应和炎症小体，发挥抗病毒作用；但在裂解复制过程中IFI16的表达调控、信号通路和功能尚无深入研究，更重要的是IFI16以及相关信号通路对KSHV感染和致病的影响和功能并不清楚。本项目研究揭示了IFI16调控KSHV裂解复制、激活自噬反应和促进KSHV诱生肿瘤的生长。自发的和化学诱导的KSHV裂解复制都明显促进IFI16的表达，抑制裂解复制所必需的RSK信号通路可逆转IFI16的表达上调，表明KSHV裂解复制通过RSK依赖的信号通路上调IFI16表达。IFI16表达显著抑制KSHV裂解复制，促使KSHV建立潜伏感染，这种抑制作用需要IFI16 PYD结构域，表明IFI16可能通过PYD结构域依赖的信号传导途径发挥抗病毒作用。进一步我们发现IFI16同样通过PYD结构域与去乙酰化酶SIRT1相互作用，特异性调控多个重要蛋白的乙酰化，进而上调自噬反应基因的表达和促进KSHV诱生肿瘤的生长。敲除或敲低IFI16表达显著降低自噬反应基因表达和缺氧诱导的HIF1a表达，进而显著抑制KSHV阳性肿瘤的生长。本项目通过深入研究IFI16在KSHV裂解复制和致肿瘤作用中的功能和机制，阐明了IFI16通过PYD结构域依赖的信号通路激活自噬反应，限制KSHV裂解复制、促进潜伏感染建立和肿瘤发生，为深入认识KSHV感染和致病机理、发展靶向IFI16及其信号通路治疗γ-疱疹病毒感染性疾病和肿瘤的治疗新策略奠定基础。