衰老过程中SIRT3对RLR抗病毒固有免疫应答的调节及机制研究

Aging is associated with a progressive decline in immune function, resulting in an increased susceptibility to infection. The impact of aging on the innate immune system remains incompletely defined. RIG-I-like receptors (RLRs) are key components of the innate immune system that detect pathogen components and trigger antiviral immune responses, which play an important role in viral clearance during infection. Our preliminary data suggest that SIRT3 has a protective role against virus infection by regulating RIG-I mediated antiviral signaling pathways. The overall significance of this proposal is to understand the regulation of RLR mediated antiviral innate immune responses by SIRT3 during aging. The expression and activation of RLRs and key signaling molecules from macrophages will be compared between young and elderly after Flu virus infection. The regulation of RLR mediated signaling pathway by deacetylase SIRT3 will be disclosed. The effect of aging on SIRT3 expression and function, which may contribute to the difference of antiviral immune responses between young and elderly, will be investigated. Our proposed studies will provide important insights into the decline of immune function during aging, which could offer novel strategies for therapeutic interventions against viral infections.

免疫系统在机体衰老过程中发生退变，导致免疫应答功能紊乱、低效。老年人抗病毒感染能力下降是免疫衰老的重要表现，但其机制尚未被完全了解。RIG-I样受体（RLR）是固有免疫系统的模式识别受体，可识别入侵病毒并启动免疫应答，在宿主清除病毒的免疫反应中起关键作用。申请人前期研究发现长寿基因家族的SIRT3可协同激活RIG-I介导的免疫应答，参与细胞抗病毒反应。因此，SIRT3功能是否随人体衰老而变化，从而影响老年人的抗病毒固有免疫应答，成为本课题的研究内容。本项目拟比较年轻人和老年人巨噬细胞RLR及其下游信号转导分子的表达水平、活化状态及在流感病毒感染后的免疫应答状况，以揭示衰老过程中RLR抗病毒固有免疫应答的特征性变化；同时探明SIRT3在衰老中的变化及作为去乙酰化酶在RLR介导的信号转导中的调控机制。将为诠释衰老削弱免疫系统抗病毒能力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。

免疫系统在机体衰老过程中发生退变，导致免疫应答功能紊乱、低效。老年人抗病毒感染能力下降是免疫衰老的重要表现，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SIRT3对抗病毒固有免疫的影响及其分子调控机制。研究发现SIRT3参与抗病毒免疫应答，Sirt3敲除小鼠和野生小鼠相比对病毒更易感，Sirt3敲除小鼠BMDM在病毒感染后产生I型干扰素显著低于野生小鼠。RIG-I 样受体（RLR）是固有免疫系统的模式识别受体，可识别入侵病毒并启动免疫应答，在宿主清除病毒的免疫反应中起关键作用。研究发现SIRT3可直接作用于RLR抗病毒固有免疫信号通路分子MAVS和TRAF3，促进MAVS/TRAF3复合物的形成，激活RLR通路。此外，SIRT3可以与线粒体蛋白SOD2相互作用，SOD2维持着细胞内ROS水平。研究发现SOD2可通过调节ROS水平影响RLR通路的激活，ROS升高导致IRF3活化程度降低，抑制抗病毒免疫应答。这和老年人体内ROS水平升高，而抗病毒免疫应答下降相吻合。本研究为诠释衰老削弱免疫系统抗病毒感染能力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。本项目开展期间已发表SCI论文两篇，Viral Immunology (通讯), Current Opinion in Immunology (一作)。