SIRT6对病毒感染引发老年人过度炎症反应的作用机制研究

Aging is associated with the dysregulation of immune system. Virus induced hyper-inflammatory responses cause significant morbidity and mortality in elderly. The innate immune system can trigger antiviral immune responses and inflammation. The homeostasis of innate immunity play an important role in sucessful aging. Our preliminary data suggest that SIRT6 can regulate innate immune response and prevent the hyper-inflammatory response during infection. The overall significance of this proposal is to understand the regulation of inflammation by SIRT6 during aging. The effect of SIRT6 on the immunopathology mediated by Influenza virus infection will be investigated. The activation of inflammation related signaling from innate immune cells will be compared between young and elderly after virus infection. The mechanism of inflammation regulation by deacetylase/ribosyltransferase SIRT6 will be disclosed. The effect of aging on SIRT6 expression and function, which may contribute to the difference of inflammatory responses between young and elderly, will be investigated. Our proposed studies will provide important insights into the dysregulation of immune function during aging, which could offer novel strategies for therapeutic interventions against viral infections.

衰老过程伴随着机体免疫功能紊乱,过度炎症反应导致的免疫病理损伤是老年人病毒感染重症、高致死率的重要原因，但其机制尚未被完全了解。天然免疫系统在调节宿主炎症反应中起到关键作用。老年人的健康老龄化需要天然免疫系统的稳态维持。申请人前期研究发现长寿基因家族成员SIRT6可调节模式识别受体介导的天然免疫应答，抑制炎症因子的过度产生。因此SIRT6是否在衰老过程中表达和功能发生变化，影响人体的免疫应答和炎症反应成为本课题的研究内容。本项目拟通过流感病毒感染模型，研究SIRT6对免疫病理损伤的影响；比较年轻人和老年人天然免疫系统在病毒感染后炎症信号通路的激活状态。探明SIRT6通过去乙酰化酶活和核糖基转移酶活作用于炎症信号通路关键分子的调控机制。阐明老年人过度炎症反应与SIRT6功能随人体衰老而变化的关系。为诠释衰老导致免疫功能紊乱的分子机制提供重要线索，为有效免疫干预手段的实施奠定基础。

衰老过程伴随着机体免疫功能紊乱，过度炎症反应导致的免疫病理损伤是老年人病毒感染重症、高致死率的重要原因。SIRT6在机体寿命和衰老过程中的作用十分重要，本课题以抗病毒固有免疫系统为切入点，研究了长寿基因家族成员SIRT6对抗病毒固有免疫的影响及其分子调控机制。研究发现SIRT6参与抗病毒免疫应答，负调控病毒诱导的炎症因子和I型干扰素的产生。SIRT6抑制抗病毒信号通路TLR和RLR激活的炎症因子表达，其机制为SIRT6的核心催化结构域和p65的DNA结合结构域相互作用，在p65的招募下，SIRT6结合到促炎因子Il6启动子区，抑制过量的炎症因子的产生。病毒感染诱导SIRT6表达上调，SIRT6通过与TLR3、RLR、cGAS-STING信号通路下游转录因子IRF3/7相互作用，抑制病毒诱导I型干扰素的产生。本研究为诠释释衰老导致免疫功能紊乱的分子机制提供重要线索，为有效免疫干预手段的实施奠定基础。本项目期间已发表SCI论文一篇，Frontiers in Cellular & Infection Microbiology (通讯)。