Mobley James A, Molyvdas Adam, Kojima Kyoko, Jilling Tamas, Li Jian-Liang, Garantziotis Stavros, Matalon Sadis
bioRxiv. 2022 Aug 31:2022.08.31.506023. doi: 10.1101/2022.08.31.506023.
The COVID-19 pandemic continues to impose a major impact on global health and economy since its identification in early 2020, causing significant morbidity and mortality worldwide. Caused by the SARS-CoV-2 virus, along with a growing number of variants that have been characterized to date, COVID-19 has led to 571,198,904 confirmed cases, and 6,387,863 deaths worldwide (as of July 15 , 2022). Despite tremendous advances in our understanding of COVID19 pathogenesis, the precise mechanism by which SARS-CoV2 causes epithelial injury is incompletely understood. In this current study, robust application of global-discovery proteomics applications combined with systems biology analysis identified highly significant induced changes by the Spike S1 protein of SARS-CoV-2 in an ATII-like Rat L2 cells that include three significant network hubs: E2F1, CREB1/ RelA, and ROCK2/ RhoA. Separately, we found that pre-treatment with High Molecular Weight Hyaluronan (HMW-HA), greatly attenuated the S1 effects. Immuno-targeted studies carried out on E2F1 and Rock2/ RhoA induction and kinase-mediated activation, in addition to cell cycle measurements, validated these observations. Taken as a whole, our discovery proteomics and systems analysis workflow, combined with standard immuno-targeted and cell cycle measurements revealed profound and novel biological changes that contribute to our current understanding of both Spike S1 and Hyaluronan biology. This data shows that the Spike S1 protein may contribute to epithelial injury induced by SARS-CoV-2. In addition, our work supports the potential benefit of HMW-HA in ameliorating SARS CoV2 induced cell injury.
自2020年初被发现以来，新冠疫情持续对全球健康和经济造成重大影响，在全球范围内导致了大量发病和死亡。新冠病毒病由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）病毒引起，随着迄今已鉴定出的变体数量不断增加，新冠病毒病在全球已导致571,198,904例确诊病例和6,387,863例死亡（截至2022年7月15日）。尽管我们对新冠病毒病发病机制的理解取得了巨大进展，但SARS-CoV-2导致上皮损伤的确切机制仍未完全明确。在本研究中，通过全面应用全球发现蛋白质组学技术并结合系统生物学分析，我们发现SARS-CoV-2的刺突S1蛋白在类II型肺泡上皮细胞样大鼠L2细胞中引起了高度显著的诱导变化，其中包括三个重要的网络枢纽：E2F1、CREB1/RelA和ROCK2/RhoA。另外，我们发现用高分子量透明质酸（HMW-HA）预处理可大大减弱S1的作用。除细胞周期测量外，针对E2F1和Rock2/RhoA诱导及激酶介导的激活进行的免疫靶向研究验证了这些观察结果。总体而言，我们的发现蛋白质组学和系统分析流程，结合标准的免疫靶向和细胞周期测量，揭示了深刻而新颖的生物学变化，有助于我们目前对刺突S1和透明质酸生物学的理解。这些数据表明，刺突S1蛋白可能导致SARS-CoV-2诱导的上皮损伤。此外，我们的研究支持HMW-HA在改善SARS-CoV-2诱导的细胞损伤方面的潜在益处。
