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

Yang Yang; Qiuyue Wu; Xueyan Liu; Hongjian Zhou; Jianzhen Lei; Lan Luo; Xinyi Xia

doi:10.1016/j.virs.2025.06.007

August 2025

. doi: 10.1016/j.virs.2025.06.007

Citation: Yang Yang, Qiuyue Wu, Xueyan Liu, Hongjian Zhou, Jianzhen Lei, Lan Luo, Xinyi Xia. SARS-CoV-2-encoded miR-nsp3-3p promotes pulmonary fibrosis by inhibiting expression of ALCAM .VIROLOGICA SINICA, 2025, 40(4) : 560-570. http://dx.doi.org/10.1016/j.virs.2025.06.007

SARS-CoV-2编码的miR-nsp3-3p抑制ALCAM表达促进肺纤维化发生的研究

杨阳 ^a ,
吴秋月 ^a ,
刘雪艳 ^a ,
周宏建 ^a ,
雷建震 ^a ,
罗兰 ^a,, ,
夏欣一 ^a,b,c,,

a 南京大学生命科学学院, 南京大学医学院附属金陵医院检验医学研究所;
b 南京大学生命分析化学国家重点实验室;
c 南方医科大学第一临床医学院金陵医院

通讯作者： 罗兰, lanluo@nju.edu.cn; 夏欣一, xinyixia@nju.edu.cn
收稿日期： 2024-09-11
录用日期： 2025-06-27

摘要

病毒编码的微小 RNA（miRNA）可在体液中被检测到，目前已知其可调控宿主基因的表达。近期有证据表明，新冠病毒（SARS-CoV-2）编码的 miRNA 可能与肺部疾病相关。肺纤维化是 SARS-CoV-2 感染患者在住院期间或出院后的重要并发症，但其潜在机制尚未完全阐明。本研究报道了一种SARS-CoV-2编码的miRNA——miR-nsp3-3p，其通过抑制活化白细胞黏附分子（ALCAM）的表达并促进上皮-间质转化，进而加剧肺纤维化的发生发展。本研究中，作者首先在临床标本中检测到miR-nsp3-3p，并发现与未感染SARS-CoV-2的对照组或轻/中度COVID-19患者相比，重症/危重症患者的咽拭子和肺泡灌洗液中该miRNA显著升高。进一步研究显示，腺相关病毒（AAV）-nsp3感染可诱导BALB/c小鼠肺纤维化，而miR-nsp3-3p拮抗剂可逆转这一过程，且ALCAM被确定为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上皮-间质转化。此外，ALCAM过表达可逆转miR-nsp3-3p诱导的EMT和纤维化。上述研究揭示了SARS-CoV-2编码的miRNA在推动肺部疾病病理进展中的关键作用，并为病毒编码的miRNA与宿主病理之间的相互作用提供了新见解。
- 微小核糖核酸
- , 新型冠状病毒
- , 肺纤维化
- , 活化淋巴细胞黏附分子
- , 上皮间质转化

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

Yang Yang ^a ,
Qiuyue Wu ^a ,
Xueyan Liu ^a ,
Hongjian Zhou ^a ,
Jianzhen Lei ^a ,
Lan Luo ^a,, ,
Xinyi Xia ^a,b,c,,

a. Institute of Laboratory Medicine, Jinling Hospital, Affiliated Hospital of Medical School, School of Life Sciences, Nanjing University, Nanjing, 210002, China;
b. State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, 210023, China;
c. Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, China

Corresponding author: Lan Luo, lanluo@nju.edu.cn Xinyi Xia, xinyixia@nju.edu.cn
Received Date: 11 September 2024
Accepted Date: 27 June 2025

Abstract

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.
- microRNA (miRNA)
- , SARS-CoV-2
- , Pulmonary fibrosis
- , Activated leukocyte cell adhesion molecule (ALCAM)
- , Epithelial-mesenchymal transition (EMT)

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Electronic Supplementary Material

10.1016j.virs.2025.06.007-ESM.docx