新冠病毒促ACE2降解并激活AngII/AT1R信号通路诱导Th17分化引发急性肺损伤的机制研究

新冠病毒结合血管紧张素酶2（ACE2）介导病毒入侵与复制。ACE2又可降解血管紧张素II（AngII）防止急性肺损伤。前期工作发现Th17和MAIT分泌的IL-17在肺炎患者肺部显著升高，诱发重症肺炎（MI2020）。新冠肺炎临床报道和死亡案例报道也指出患者血液中高比例Th17细胞分化，但具体分子机制尚未明确。预实验发现①Spike蛋白促进胞膜表面的ACE2经自噬溶酶体途径降解，降低ACE2的表达；②新冠肺炎患者血浆中AngII显著升高；③AngII诱导T细胞的Th17分化。我们提出如下科学假设：病毒诱导ACE2的胞吞促进其自噬降解，上调AngII水平；AngII-AT1R信号轴激活Th17通路介导急性肺损伤。拟采用细胞和小鼠感染模型，阐明病毒感染引起ACE2自噬降解，上调AngII-AT1R信号轴激活Th17通路的机制。本研究有望揭示机体自噬与新冠感染的关系以及新冠感染的免疫病理机制。

During SARS-CoV-2 infection, ACE2 acts as a host receptor to mediate virus invasion and replication. Angiotensin converting enzyme 2 (ACE2) degrades angiotensin II (AngII) to prevent acute lung injury. We have previously showed that IL-17 produced by Th17 and MAIT is significantly increased in the lungs of pneumonia patients and mediates pneumonia severity (MI2020). The clinical report of COVID-19 patients and a death case report showed increased proportion of Th17 cells in blood, but the underlying mechanism remained unclear. Recently, we found that ①Spike protein promotes the degradation of ACE2 on cell membrane surface by autophagy-lysosome pathway， lowering ACE2 expression; ② AngII was significantly increased in the plasma of COVID-19 patients; ③ AngII induces Th17 differentiation. We raised the following hypothesis: The virus induce endocytosis of ACE2 to promote its autophagic degradation, leading to elevated level of AngII. AngII-AT1R signal axis activate the Th17 differentiation to mediate acute lung injury. We propose to use SARS-CoV-2 infected cells and mouse models to clarify the mechanism of viral infection mediated ACE2 autophagy degradation and AngII-AT1R signal axis mediated acute lung injury. This study will reveal the association of host autophagy and SARS-CoV-2 infection, as well as the immuno-pathogenic mechanism of SARS-CoV-2 infection.