SARS-CoV-2-encoded miR-nsp3-3p promotes pulmonary fibrosis by inhibiting expression of ALCAM

• Published in: Virologica Sinica Vol. 40; no. 4; pp. 560 - 570
• Main Authors: Yang, Yang, Wu, Qiuyue, Liu, Xueyan, Zhou, Hongjian, Lei, Jianzhen, Luo, Lan, Xia, Xinyi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2025
• Subjects: Activated leukocyte cell adhesion molecule (ALCAM); Activated-Leukocyte Cell Adhesion Molecule; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; COVID-19 - complications; COVID-19 - genetics; COVID-19 - pathology; COVID-19 - virology; Epithelial-mesenchymal transition (EMT); Epithelial-Mesenchymal Transition - genetics; Female; Fetal Proteins - genetics; Fetal Proteins - metabolism; Humans; Male; Mice; Mice, Inbred BALB C; microRNA (miRNA); MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Pulmonary fibrosis; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Pulmonary Fibrosis - virology; RNA, Viral - genetics; RNA, Viral - metabolism; SARS-CoV-2; SARS-CoV-2 - genetics; SARS-CoV-2; Epithelial-mesenchymal transition (EMT); Pulmonary fibrosis; microRNA (miRNA); Activated leukocyte cell adhesion molecule (ALCAM)
• ISSN: 1995-820X; 1995-820X
• DOI: 10.1016/j.virs.2025.06.007

microRNAs (miRNAs) derived from viruses, have been detected in body fluids and are known to regulate the expression of host genes. Recent evidence indicates that SARS-CoV-2-encoded miRNAs could contribute to pulmonary disease. Pulmonary fibrosis is an important complication in SARS-CoV-2 infected patients, either during hospitalization or after discharge, however, the underlying mechanisms are not fully elucidated. Here, we report a SARS-CoV-2-encoded miRNA, miR-nsp3-3p, facilitates host pulmonary fibrosis by inhibiting expression of activated leukocyte cell adhesion molecule (ALCAM) and promoting epithelial-mesenchymal transition (EMT). First, we detected miR-nsp3-3p in clinical specimens and found it was remarkably increased in throat swabs and alveolar lavage fluids from severe/critical COVID-19 patients compared to control groups or mild/moderate patients. We further revealed that adeno-associated virus (AAV)-nsp3 infection can induce pulmonary fibrosis in BALB/c mice while miR-nsp3-3p antagomirs can reverse that, and ALCAM was found to be as a target gene of miR-nsp3-3p. miR-nsp3-3p overexpression can inhibit the expression of ALCAM and promote EMT of pulmonary epithelial cells. Moreover, overexpression of ALCAM can reverse the miR-nsp3-3p-induced EMT and fibrosis. These findings highlight the essential role of SARS-CoV-2-encoded miRNAs in promoting the pathological progression of lung disease, and provide novel insights into the interactions between viral miRNAs and host pathology. •SARS-CoV-2 encoded miR-nsp3-3p were highly expressed in severe/critical COVID-19 patients.•miR-nsp3-3p exerts a post-transcriptional regulatory effect on ALCAM by binding to the 3′UTR of ALCAM.•miR-nsp3-3p promotes the occurrence of EMT in lung epithelial cells by downregulating ALCAM.•miR-nsp3-3p induces pulmonary fibrosis in mice by promoting EMT.