Jian-Bang Xu,Wei-Jie Guan ORCID: orcid.org/0000-0001-5463-391X,Yi-Lin Zhang ORCID: orcid.org/0000-0001-5350-8279,Zhuo-Er Qiu,Lei Chen ORCID: orcid.org/0000-0002-9488-1173,Xiao-Chun Hou,Junqing Yue,Yu-Yun Zhou,Jie Sheng,Lei Zhao,Yun-Xin Zhu,Jing Sun,Jincun Zhao ORCID: orcid.org/0000-0003-2515-5589,Wen-Liang Zhou &…Nan-Shan Zhong

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.

https://doi.org/10.1038/s41392-024-01753-z

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