基于病毒包膜S1蛋白衍生的淀粉样多肽促进病毒感染在危重症新冠肺炎中致病机制的研究

危重症新冠肺炎的病死率高达50%，疾病进展与病人体内持续高的病毒载量和细胞因子风暴密切相关。我们发现新冠病毒S1蛋白衍生的淀粉样多肽，其能自发形成淀粉样纤维，显著地促进SARS-CoV-2假病毒的感染，淀粉样多肽也能上调巨噬细胞炎症因子的表达；在S蛋白介导细胞融合体系上清液及感染者血液中都观察到淀粉样纤维；提示S1蛋白衍生的淀粉样多肽与COVID-19的发生发展密切相关。本研究拟通过体内外实验确证S1蛋白衍生的淀粉样多肽的天然存在及其促进病毒感染的作用及机制；构建肺部表达S1蛋白的转基因小鼠，研究S1蛋白体内降解的淀粉样多肽，通过基因测序及生化实验探讨S1蛋白体内降解的机制及相关信号通路；探讨淀粉样多肽诱导肺部炎症的作用及机制。研究将阐明S1蛋白衍生的淀粉样多肽通过促进病毒感染及致炎的双重作用在COVID-19中的致病新机制，为开发抗病毒药物和疫苗提供新思路和新靶点。

The fatality rate of critical COVID-19 is about 50%, which might result from the persistent high viral load and cytokine storm in vivo. We found that naturally occurred amyloidogenic peptides derived from the S1 protein of SARS-CoV-2 could spontaneously form amyloid fibrils, which can significantly enhance the infection of SARS-CoV-2 pseudoviruses. As well, these amyloidogenic peptides could up-regulate the expression of inflammation factors. Amyloid fibrils could be found in the supernatants of the cell fusion system and the blood of COVID-19 patient. These results suggested that amyloidogenic peptides derived from S1 protein play important role in the pathogenesis of COVID-19. We aim to confirm the occurrence of S1 protein derived amyloidogenic peptides and their effects to enhance viral infection both in vitro and in vivo. We also want to construct transgenic mice that overexpress S1 protein in the lung, so as to investigate the degradation process of S1 protein in vivo, to explore the signal pathway involved based on the results of genomic sequencing and biochemical experiments. The effects and the mechanism of amyloidogenic peptides induced inflammation in the lung will be explored. This study will reveal the bi-functional effects of the S1 protein derived amyloid fibrils in the pathogenesis in COVID-19 by promoting viral infection and induction of inflammation. The result will provide new drug target for effective antiviral treatment and vaccine.