SARS-CoV-2 spike promotes inflammation and apoptosis through autophagy by ROS-suppressed PI3K/AKT/mTOR signaling

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1867

Article

Li, Fei¹  Li, Jingyao¹  Wang, Pei-Hui^2,3  Yang, Nanyan¹  Huang, Junyu¹  Ou, Jinxin¹  Xu, Ting¹  Zhao, Xin¹  Liu, Taoshu¹  Huang, Xueying¹  Wang, Qinghuan¹  Li, Miao¹  Yang, Le¹  Lin, Yunchen¹  Cai, Ying¹  Chen, Haisheng¹  Zhang, Qing^1,4 

[1] Sun Yat Sen Univ, Sch Life Sci, State Key Lab Biocontrol, Guangzhou 510275, GD, Peoples R China

[2] Shandong Univ, Cheeloo Coll Med, Key Lab Expt Teratol, Minist Educ, Jinan, Peoples R China

[3] Shandong Univ, Cheeloo Coll Med, Adv Med Res Inst, Jinan, Peoples R China

[4] Inst Sun Yat Sen Univ Shenzhen, Shenzhen, Peoples R China

关键词: SARS-CoV-2;    Inflammation;    Autophagy;    Apoptosis;    Reactive oxygen species;   

DOI  :  10.1016/j.bbadis.2021.166260

来源: Elsevier

【 摘 要 】

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection-induced inflammatory responses are largely responsible for the death of novel coronavirus disease 2019 (COVID-19) patients. However, the mechanism by which SARS-CoV-2 triggers inflammatory responses remains unclear. Here, we aimed to explore the regulatory role of SARS-CoV-2 spike protein in infected cells and attempted to elucidate the molecular mechanism of SARS-CoV-2-induced inflammation. Methods: SARS-CoV-2 spike pseudovirions (SCV-2-S) were generated using the spike-expressing virus packaging system. Western blot, mCherry-GFP-LC3 labeling, immunofluorescence, and RNA-seq were performed to examine the regulatory mechanism of SCV-2-S in autophagic response. The effects of SCV-2-S on apoptosis were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), Western blot, and flow cytometry analysis. Enzyme-linked immunosorbent assay (ELISA) was carried out to examine the mechanism of SCV-2-S in inflammatory responses. Results: Angiotensin-converting enzyme 2 (ACE2)-mediated SCV-2-S infection induced autophagy and apoptosis in human bronchial epithelial and microvascular endothelial cells. Mechanistically, SCV-2-S inhibited the PI3K/AKT/mTOR pathway by upregulating intracellular reactive oxygen species (ROS) levels, thus promoting the autophagic response. Ultimately, SCV-2-S-induced autophagy triggered inflammatory responses and apoptosis in infected cells. These findings not only improve our understanding of the mechanism underlying SARS-CoV-2 infection-induced pathogenic inflammation but also have important implications for developing anti-inflammatory therapies, such as ROS and autophagy inhibitors, for COVID-19 patients.

【 授权许可】

Free