共生菌维持肺免疫稳态及其抵抗流感病毒急性肺损伤的机制研究

"Cytokine storm" effect-mediated excessive immune response is a major contributor to the acute lung injury during influenza virus infection. However, there was no effective way to control this harmful effect until now. Lung has the ability to maintain immune homeostasis, so exploring both regulatory immune cells and related key molecules in the lung may provide effective ways to attenuate "cytokine storm" effect-mediated injury. In previous study, we found that SPF mice were more sensitive to influenza-caused lung injury than mice lived in natural environment, and priming with commensal bacteria such as Staphylococcus aureus colonized in the respiratory tract could protect mice against influenza-caused lung injury and death. In this study, we aim to systematically verify the function of commensal bacteria in the respiratory tract on maintaining lung immune homeostasis and controlling excessive immune response, to explore the regulatory innate immune cell subsets maintaining lung immune homeostasis, and to ascertain the source, differentiation and function of this cell subset. Based on above, we will further study the molecular mechanism of the interaction between the core composition of commensal bacteria and the receptor expressed on regulator innate immune cell subsets, and further reveal the key functional molecules by which regulatory innate immune cells negative regulate the pathologic inflammatory cells, which will provide new therapeutic idea for preventing influenza-caused lung injury.

过度免疫应答的"细胞因子风暴"效应是流感导致急性肺损伤的主要原因，然而目前尚没有控制这种过度免疫应答的有效手段。肺脏具有维持自身免疫稳态的能力，寻找肺脏负相免疫细胞及其关键分子可为缓解"细胞因子风暴"导致的损伤提供有效手段。我们在数年的前期研究中发现，自然环境饲养小鼠和SPF环境饲养小鼠对流感导致急性肺损伤的敏感性存在巨大差异；呼吸道共生菌，例如金黄色葡萄球菌，致敏能够保护小鼠抵抗流感病毒导致的肺损伤和死亡。本研究旨在进一步系统验证小鼠呼吸道共生菌维持肺脏免疫稳态并控制过度免疫应答的能力；寻找维持肺脏免疫稳态的调节性天然免疫细胞或亚群，并探明其来源、分化和功能调控等特性。在上述基础上，深入研究共生菌的核心成分与调节性天然免疫细胞上相应受体进行识别活化的分子机制，揭示调节性天然免疫细胞负相调节病理性炎症细胞的关键功能分子，为防治流感急性肺损伤提供新思路。

在机体的正常生理活动中，肺脏的主要功能是负责机体与外界环境的气体交换。肺脏的这种特殊生理功能决定其成为一个对外开放的器官，这就使得肺脏时刻接受来自外界环境中非己物质以及各种微生物的刺激。然而，令人惊讶的是，尽管呼吸道拥有巨大的表面并且每天有大量的感染因子伴随空气进入呼吸道，但是呼吸道炎症反应却很少发生。人的上呼吸道同肠道一样，有大量共生菌的寄居，宿主与共生菌之间的相互作用往往是互惠互利的。本研究采用金黄色葡萄球菌（S. aureus）滴鼻致敏小鼠建立S. aureus上呼吸道共生模型，之后利用该模型探讨了呼吸道共生菌对流感病毒感染的影响。本研究发现S. aureus致敏能够保护小鼠抵抗PR8感染导致的死亡，这种保护作用依赖于减轻PR8感染诱导的免疫损伤而并不依赖于抑制病毒的增殖。在S. aureus致敏过程中，TLR2活化所营造的肺泡环境能够促进AMs向M2型巨噬细胞极化，进而抑制PR8感染过程中炎症细胞的招募和增殖。