摘要 : SARS-CoV-2,the culprit pathogen of COVID-19,elicits prominent immune responses and cytokine storms.Intracellular Cl^(−)is a crucial regulator of host defense,whereas the role of Cl^(−)signaling pathway in modulating pulmonary infl... 展开 SARS-CoV-2,the culprit pathogen of COVID-19,elicits prominent immune responses and cytokine storms.Intracellular Cl^(−)is a crucial regulator of host defense,whereas the role of Cl^(−)signaling pathway in modulating pulmonary inflammation associated with SARS-CoV-2 infection remains unclear.By using human respiratory epithelial cell lines,primary cultured human airway epithelial cells,and murine models of viral structural protein stimulation and SARS-CoV-2 direct challenge,we demonstrated that SARS-CoV-2 nucleocapsid(N)protein could interact with Smad3,which downregulated cystic fibrosis transmembrane conductance regulator(CFTR)expression via microRNA-145.The intracellular Cl^(−)concentration([Cl^(−)]i)was raised,resulting in phosphorylation of serum glucocorticoid regulated kinase 1(SGK1)and robust inflammatory responses.Inhibition or knockout of SGK1 abrogated the N protein-elicited airway inflammation.Moreover,N protein promoted a sustained elevation of[Cl^(−)]i by depleting intracellular cAMP via upregulation of phosphodiesterase 4(PDE4).Rolipram,a selective PDE4 inhibitor,countered airway inflammation by reducing[Cl^(−)]i.Our findings suggested that Cl^(−)acted as the crucial pathological second messenger mediating the inflammatory responses after SARS-CoV-2 infection.Targeting the Cl^(−)signaling pathway might be a novel therapeutic strategy for COVID-19. 收起