Yang Yang, Wu Qiuyue, Liu Xueyan, Zhou Hongjian, Lei Jianzhen, Luo Lan, Xia Xinyi
Institute of Laboratory Medicine, Jinling Hospital, Affiliated Hospital of Medical School, School of Life Sciences, Nanjing University, Nanjing, 210002, China.
Institute of Laboratory Medicine, Jinling Hospital, Affiliated Hospital of Medical School, School of Life Sciences, Nanjing University, Nanjing, 210002, China.
Virol Sin. 2025 Jul 1. 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.
源自病毒的微小RNA（miRNA）已在体液中被检测到，并且已知其可调节宿主基因的表达。最近的证据表明，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）编码的miRNA可能导致肺部疾病。肺纤维化是SARS-CoV-2感染患者在住院期间或出院后出现的一种重要并发症，然而，其潜在机制尚未完全阐明。在此，我们报告一种SARS-CoV-2编码的miRNA，即miR-nsp3-3p，它通过抑制活化白细胞细胞黏附分子（ALCAM）的表达并促进上皮-间质转化（EMT）来促进宿主肺纤维化。首先，我们在临床标本中检测到miR-nsp3-3p，发现与对照组或轻症/中症患者相比，其在重症/危重症2019冠状病毒病（COVID-19）患者的咽拭子和肺泡灌洗液中显著增加。我们进一步发现，腺相关病毒（AAV）-nsp3感染可在BALB/c小鼠中诱导肺纤维化，而miR-nsp3-3p拮抗剂可逆转这一过程，并且发现ALCAM是miR-nsp3-3p的靶基因。miR-nsp3-3p过表达可抑制ALCAM的表达并促进肺上皮细胞的EMT。此外，ALCAM过表达可逆转miR-nsp3-3p诱导的EMT和纤维化。这些发现突出了SARS-CoV-2编码的miRNA在促进肺部疾病病理进展中的重要作用，并为病毒miRNA与宿主病理学之间的相互作用提供了新的见解。
