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

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1867; no. 12; p. 166260
• Main Authors: Li, Fei, Li, Jingyao, Wang, Pei-Hui, Yang, Nanyan, Huang, Junyu, Ou, Jinxin, Xu, Ting, Zhao, Xin, Liu, Taoshu, Huang, Xueying, Wang, Qinghuan, Li, Miao, Yang, Le, Lin, Yunchen, Cai, Ying, Chen, Haisheng, Zhang, Qing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2021; The Author(s). Published by Elsevier B.V
• Subjects: Animals; Apoptosis; Apoptosis - immunology; Autophagy; Autophagy - physiology; Cell Line; Chlorocebus aethiops; COVID-19 - metabolism; Endothelial Cells - metabolism; HEK293 Cells; Humans; Inflammation; Inflammation - immunology; Inflammation - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; SARS-CoV-2; SARS-CoV-2 - pathogenicity; Signal Transduction - immunology; Spike Glycoprotein, Coronavirus - immunology; Spike Glycoprotein, Coronavirus - metabolism; TOR Serine-Threonine Kinases - metabolism; Vero Cells; Reactive oxygen species; IL; Inflammation; MERS-CoV; Co-IP; Autophagy; COVID-19; ACE2; SARS-CoV-2; DEGs; TUNEL; TNF-α; RT-PCR; ROS; KEGG; 3-MA; Apoptosis; ELISA
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2021.166260

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. 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. 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. •SARS-CoV-2 spike triggers autophagy and apoptosis in ACE2-expressing cells.•SARS-CoV-2 spike induces autophagy through ROS-suppressed PI3K/AKT/mTOR pathway.•SARS-CoV-2 spike-induced autophagy promotes inflammatory responses and apoptosis.