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

  • Biochim Biophys Acta Mol Basis Dis. 2021 Dec 1;1867(12):166260. doi: 10.1016/j.bbadis.2021.166260.
Fei Li  1 ,  Jingyao Li  1 ,  Pei-Hui Wang  2 ,  Nanyan Yang  1 ,  Junyu Huang  1 ,  Jinxin Ou  1 ,  Ting Xu  1 ,  Xin Zhao  1 ,  Taoshu Liu  1 ,  Xueying Huang  1 ,  Qinghuan Wang  1 ,  Miao Li  1 ,  Le Yang  1 ,  Yunchen Lin  1 ,  Ying Cai  1 ,  Haisheng Chen  1 ,  Qing Zhang  3
Affiliations
  • 1. State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
  • 2. Key Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 3. State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China; Institute of Sun Yat-sen University in Shenzhen, Shenzhen, China. Electronic address: [email protected].
PMID: 34461258 DOI: 10.1016/j.bbadis.2021.166260
Abstract

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.

Keywords
Apoptosis; Autophagy; Inflammation; Reactive oxygen species; SARS-CoV-2.
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