RLR激活介导的代谢重编对抗病毒固有免疫的调节

Cytosolic nucleic acid sensing-mediated innate anti-viral immunity plays a significant role in defending against viral infections. To further understand the molecular regulatory circuitry underlying the latter process is highly warranted. Using RLR-mediated innate immune activation as a major model, we propose that RLR activation can trigger metabolic reprogramming to limit the biosynthetic flux, and thus inhibit viral replication. Our preliminary data showed that PFKFB3, a critical regulator of glucose metabolism, is down-regulated by RLR signaling. By using gain-of-function and loss-of-function approaches, we will begin to test the importance of PFKFB3 inhibition in RLR-mediated metabolic reprogramming and anti-viral defense. Additionally, we will study the mechanisms underlying RLR-triggered down-regulation of PFKFB3. Furthermore, we will actively seek evidence for direct connections between PFKFB3-associated metabolic changes and the delicate molecular antiviral programs. Using such a metabolic entry point, our work may facilitate identification of novel regulatory points in antiviral innate immunity. Lastly, we will attempt to address the possibility that under the condition of RLR and TLR co-activation, RLR-mediated inhibition of PFKFB3, whose activity is important for TLR response, may represent a molecular mechanism whereby anti-viral immunity interferes with anti-bacteria immunity.

胞浆核酸识别介导的固有免疫应答是机体对抗病毒的重要系统。对其在各个层面分子调控的研究有重要基础及临床价值。本课题利用RLR通路激活为主要研究对象，提出该通路激活后会下调糖代谢核心调控酶PFKFB3而产生限制生物合成的代谢重编，从而抑制病毒扩增。我们将利用PFKFB3的功能获得或功能丧失的模型，首先从代谢学角度分析其调控的重要性。我们也将对RLR通路导致PFKFB3下调的机制作细致分析。在PFKFB3调控细胞抗病毒能力的机制研究中，我们将着重于探索PFKFB3及相关代谢靶点与抗病毒免疫应答程序间的直接的连接，以期挖掘出前所未知的调控机制。此外，我们将在体内病毒感染模型中验证在细胞学上的结果。最后，我们将试图探讨是否在RLR与TLR共激活状态下，RLR对PFKFB3的抑制会阻碍需要其活性上调的TLR免疫应答。我们的结果将有可能首次揭示抗病毒免疫可以从能量代谢角度干扰抗细菌免疫。

免疫系统与代谢调节密切相关。然而，这两个系统之间的联系机制还仍不清楚。在本研究中，我们着手研究了抗病毒固有免疫和细胞代谢之间的关系。我们发现，细胞质病毒识别通过进一步诱导IFN信号通路，导致巨噬细胞选择性的糖酵解上调。后者涉及IFN所诱导的关键糖酵解调节酶PFKFB3。PFKFB3驱动的糖酵解通过从代谢上促进巨噬细胞对病毒感染细胞的吞噬和清除，提高了巨噬细胞特异性的外源性抗病毒活性。这些PFKFB3相关的抗病毒机制，与IFN在巨噬细胞中选择性地诱导其表达有很好的对应。此外，我们在呼吸道合胞病毒感染的小鼠模型中证实了PFKFB3的抗病毒功能，以及它在免疫细胞中发挥的特殊作用。我们的发现建立了糖酵解的一种抗病毒、免疫代谢相关的新功能，可能具有临床意义。此外，我们还利用另外两个基因模型进一步探讨了PFKFB3在巨噬细胞中的调控作用。