Abstract
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.
【초록키워드】 COVID-19, SARS-CoV-2, immune response, Inflammatory responses, SARS-COV-2 infection, microRNA, fibrosis, inhibition, glucocorticoid, pulmonary inflammation, Protein, serum, pathogen, cells, immune responses, N protein, Phosphorylation, Smad3, epithelial cells, murine model, cystic fibrosis, structural protein, signaling pathway, inhibitor, expression, epithelial, therapeutic strategy, CFTR, Inflammatory response, Concentration, cell lines, host defense, SGK1, Cytokine storms, epithelial cell, second messenger, Airway inflammation, knockout, murine models, upregulation, transmembrane, CAMP, selective, SARS-CoV-2 nucleocapsid, Defense, targeting, Intracellular, Host, phosphodiesterase, Rolipram, robust, resulting, raised, reducing, demonstrated, suggested, elicit, regulated, human airway epithelial, depleting, sustained, abrogated, downregulated, promoted, modulating, 【제목키워드】 Protein, hyperinflammation, Trigger, respiratory epithelium,