IL-4/13-STAT6信号通路影响卡波氏肉瘤病毒感染与致病的分子机制

Kaposi's sarcoma-associated herpesvirus (KSHV) is tightly associated with many human malignancies including KS and PEL. How KSHV infection persists and causes diseases is not fully understood. Currently there is no effective therapeutic target for KSHV associated diseases. STAT6 is a member of signal transducer and activator of transcription (STAT) family, and involves in regulation of IL-4 and IL-13-induced pleiotropic function response of immune cells. Accumulative evidences showed that IL-4/13 and STAT6 signaling pathway plays a critical role in viral infection and pathogenesis which is a hot topic in the field. It has been demonstrated by us and other researchers that IL-4 is associated with KSHV life cycle control, but how KSHV utilizes IL-4/13-STAT6 signaling pathway to establish persistent infection and induce tumorigenesis remains unclear. Based on our preliminary work, we propose here to further elucidate the molecular mechanisms of how KSHV establishes and maintains latent infection through its selectively regulating IL-4/IL-13 and their upstream and downstream factors in STAT6 signaling pathway, and address how this leads to immune escape, survival and growth of KSHV-infected cells. This study will provide potential application of interference IL-4/13-STAT6 signaling pathway to against KSHV-associated tumor growth. The implementation of this proposal will also provide potential targets and strategies for the diagnosis and treatment of KSHV-associated cancers.

卡波氏肉瘤病毒(KSHV)与卡波氏肉瘤和原发渗出性淋巴瘤等多种人恶性肿瘤密切相关，但其如何持续感染乃至致瘤的机制至今尚未完全清楚，且临床上无相应的靶向疗法。STAT6参与白介素IL-4和IL-13诱导的免疫细胞多效性功能应答调控。累积数据表明IL-4/13-STAT6信号通路在病毒致病中起关键性作用，成为目前国内外研究热点。我们及同行前期研究发现IL-4与KSHV生命周期调控有关，但KSHV如何篡改IL-4/13-STAT6信号以持续感染并影响肿瘤发生的机理仍未知。本课题拟以多个感染KSHV的细胞类型为研究对象，体内外深入探讨KSHV如何利用IL-4/IL-13应答异同和STAT6上下游信号，建立和维持潜伏感染并导致宿主细胞免疫逃逸、存活和增殖等恶性行为的致病分子机制；同时明确其关键节点干预的潜在拮抗作用。本项目的实施将为KSHV相关肿瘤诊治提供新靶点及策略。

卡波氏肉瘤病毒(KSHV)与卡波氏肉瘤和原发渗出性淋巴瘤等多种人恶性肿瘤密切相关。白介素IL-4/13介导STAT6应答信号通路调控了免疫细胞多效性功能，并在病毒致病中起关键作用。但是，对于KSHV 怎样调控IL-4/13-STAT6信号通路建立和维持持续感染和致病机理尚未完全清楚。经过四年研究，我们取得了如下进展：1) 解析了KSHV不同感染状态对IL-4/IL-13受体及效应因子表达激活的影响；2)阐明了阻断IL-4激活STAT6信号对KSHV建立并维持潜伏感染及宿主细胞逃避免疫识别的作用及潜在机制；3)明确了KSHV选择性调控IL-13介导STAT6组成型激活的因素及其在宿主细胞存活和增殖中的作用；4) 揭示了KSHV篡改STAT6相关基因谱及STAT6信号关闭对KSHV重新激活的影响和作用机制；5) 阐明了STAT6信号不同节点干预对抑制KSHV相关肿瘤生成的潜在作用和机制。我们的研究将有利于更好地理解KSHV及其它疱疹病毒持续感染和致病机制，为抗KSHV相关肿瘤诊治提供新靶点和策略。