SARS-CoV-2 envelope protein impairs airway epithelial barrier function and exacerbates airway inflammation via increased intracellular Cl- concentration

  • Signal Transduct Target Ther. 2024 Mar 25;9(1):74. doi: 10.1038/s41392-024-01753-z.
Jian-Bang Xu  #  1 ,  Wei-Jie Guan  #  2  3  4 ,  Yi-Lin Zhang  #  5  6 ,  Zhuo-Er Qiu  5 ,  Lei Chen  5 ,  Xiao-Chun Hou  5 ,  Junqing Yue  1  7 ,  Yu-Yun Zhou  5 ,  Jie Sheng  5 ,  Lei Zhao  1  8 ,  Yun-Xin Zhu  5 ,  Jing Sun  1  7 ,  Jincun Zhao  1  7 ,  Wen-Liang Zhou  9 ,  Nan-Shan Zhong  10  11
Affiliations
  • 1. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Respiratory and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China.
  • 2. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Respiratory and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China. [email protected].
  • 3. Department of Thoracic Surgery, Guangzhou Institute for Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China. [email protected].
  • 4. Guangzhou National Laboratory, Guangzhou, P. R. China. [email protected].
  • 5. School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China.
  • 6. Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China.
  • 7. Guangzhou National Laboratory, Guangzhou, P. R. China.
  • 8. Department of Physiology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, P. R. China.
  • 9. School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China. [email protected].
  • 10. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Respiratory and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, P. R. China. [email protected].
  • 11. Guangzhou National Laboratory, Guangzhou, P. R. China. [email protected].
  • # Contributed equally.
PMID: 38528022 DOI: 10.1038/s41392-024-01753-z
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Infection disrupts the epithelial barrier and triggers airway inflammation. The envelope (E) protein, a core virulence structural component of coronaviruses, may play a role in this process. Pathogens could interfere with transepithelial Cl- transport via impairment of the cystic fibrosis transmembrane conductance regulator (CFTR), which modulates nuclear factor κB (NF-κB) signaling. However, the pathological effects of SARS-CoV-2 E protein on airway epithelial barrier function, Cl- transport and the robust inflammatory response remain to be elucidated. Here, we have demonstrated that E protein down-regulated the expression of tight junctional proteins, leading to the disruption of the airway epithelial barrier. In addition, E protein triggered the activation of Toll-like Receptor (TLR) 2/4 and downstream c-Jun N-terminal kinase (JNK) signaling, resulting in an increased intracellular Cl- concentration ([Cl-]i) via up-regulating phosphodiesterase 4D (PDE4D) expression in airway epithelial cells. This elevated [Cl-]i contributed to the heightened airway inflammation through promoting the phosphorylation of serum/glucocorticoid regulated kinase 1 (SGK1). Moreover, blockade of SGK1 or PDE4 alleviated the robust inflammatory response induced by E protein. Overall, these findings provide novel insights into the pathogenic role of SARS-CoV-2 E protein in airway epithelial damage and the ongoing airway inflammation during SARS-CoV-2 Infection.

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