MSK-2调控细胞自噬在RSV感染肺损伤机制的研究

Respiratory syncytial virus (RSV) is critical pathogen of severe airway disease casing death in infants and the elder people. To date, There is still no vaccine and limited specific drugs in markets, attributing to the mechanisms of RSV-induced lung injury remaining elusive. Previously, we’ve achieved the database associated with RSV via whole human genome siRNA screening，which described comprehensively the RSV infection. From database, we found that MSK-2 could negatively regulate the inflammatory cytokines, and also promoted the formation of autophagy induced by RSV. Interestingly, if RSV-induced autophagy were intervened by inhibitor 3-MA , the inflammatory cytokines increased significantly. In the project, we would investigate the molecular mechanism of MSK-2-promting autophagy. And we have knew that autophagy played a critical role in inhibiting inflammatory cytokines. This project would figure out the inner link of “MSK-2, autophagy and inflammatory cytokines”Therefore, it hypothesis that” MSK-2-autophagy-inflammatory cytokines”, which provides new idea for the pathogenesis of RSV-induced lung injury. Also the hypothesis could lay a theoretical foundation for the design of rational and effective therapeutic strategy for RSV.

呼吸道合胞病毒是造成婴幼儿及老年人因下呼吸道疾病死亡的重要病原体。迄今，尚无批准的RSV疫苗和特异性治疗药物，归其原因是RSV感染介导肺损伤机制尚未阐述清楚。前期我们建立RSV感染致病关键因子基因数据库，能够较为全面地描绘其感染过程。从中我们发现核糖体蛋白S6激酶-4（MSK-2）不仅能调控RSV介导的炎症反应，而且促进RSV诱导自噬小体形成。有趣的是，干预RSV诱导自噬增强炎症应答。本课题进一步对MSK-2促自噬分子机制进行探讨，基于自噬抑制炎性因子变化，开展对MSK-2、自噬与炎症反应的内在联系深入探究，提出“MSK-2促进RSV诱导自噬进而调节炎症反应”，即“MSK-2-自噬-炎症”假说，为RSV的科学防控提供理论依据。

呼吸道合胞病毒是造成婴幼儿及老年人因下呼吸道疾病死亡的重要病原体。迄今，尚无批准的RSV疫苗和特异性治疗药物，归其原因是RSV感染介导肺损伤机制尚未阐述清楚。前期通过人类全基因组siRNA的筛选及初步细胞实验，发现核糖体蛋白S6激酶-4（MSK-2）不仅能调控RSV介导的炎症反应，而且促进RSV诱导自噬小体形成。在该项目资助下，本研究首先成功构建了MSK2-/-基因敲除小鼠，并在体内敲除小鼠模型，明确MSK-2负调控在RSV感染导致的肺损伤；不仅如此，我们还发现MSK-2同样可以负调控SARS-CoV-2感染导致的肺损伤；制备重组MSK-2蛋白，通过体内干预进一步明确MSK-2可缓解RSV诱导的肺损伤。另一方面，在小鼠感染模型上，进一步明确MSK-2可参与RSV诱导的自噬小体的形成。在此基础上，通过利用转录本测序及生物信息学分析，描绘MSK-2在RSV感染诱导的肺损伤的功能图；进一步推断AMPK介导的信号转导通路可能为连接“MSK-2-自噬-炎症因子”的纽带。综上，本研究初步阐述了 “MSK-2促进RSV诱导自噬进而调节炎症反应”，即“MSK-2-自噬-炎症”假说，为RSV的科学防控提供理论依据。

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