Compromised efferocytosis during aging is related to COVID-19 severity in mice

Xianliang Ke; Xian Lin; Jin Wang; Minqi Chen; Xiaoqin Jian; Chang Ye; Quanjiao Chen

doi:10.1016/j.virs.2025.05.008

June 2025

. doi: 10.1016/j.virs.2025.05.008

Citation: Xianliang Ke, Xian Lin, Jin Wang, Minqi Chen, Xiaoqin Jian, Chang Ye, Quanjiao Chen. Compromised efferocytosis during aging is related to COVID-19 severity in mice .VIROLOGICA SINICA, 2025, 40(3) : 419-429. http://dx.doi.org/10.1016/j.virs.2025.05.008

衰老过程中胞葬作用受损与小鼠COVID-19重症程度相关

柯贤良 ^a,b ,
林显 ^a,b,c ,
王瑨 ^d ,
陈敏琪 ^e ,
蹇晓沁 ^a,b,f ,
叶昶 ^a,b,f ,
陈全姣 ^a,b,,

a 中国科学院武汉病毒研究所特殊病原体与生物安全重点实验室;
b 中国科学院武汉病毒研究所生物安全大科学中心;
c 湖北省江夏实验室;
d 中山大学附属第三医院内分泌与代谢病学科;
e 中山大学中山医学院教育部干细胞和组织工程重点实验室;
f 中国科学院大学

通讯作者： 陈全姣, chenqj@wh.iov.cn
收稿日期： 2025-01-25
录用日期： 2025-05-12

摘要

衰老是2019冠状病毒（COVID-19）致病的最大风险因素之一。老年个体感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）后出现的免疫应答失调是导致疾病重症化的关键因素，但其内在机制尚不明确。本研究成功构建了老年COVID-19小鼠模型，精准模拟了老年患者的重症发展进程。通过单细胞转录组分析发现，感染肺组织呈现独特的免疫细胞分布格局，并伴随过度激活的炎症反应，这种现象在老年小鼠中尤为显著。与年轻小鼠相比，老年小鼠表现出广泛的中性粒细胞活化、NETosis（中性粒细胞胞外诱捕网形成），以及肺泡巨噬细胞（AM）数量急剧减少。更重要的是，作为胞葬作用（efferocytosis）的核心执行者，老年小鼠的AM表现出胞葬作用相关基因特征减弱及多种胞葬受体下调。深入研究表明，无论经历凋亡还是NETosis的中性粒细胞，其胞葬作用在SARS-CoV-2感染后均显著受损。鉴于胞葬作用是炎症消退的关键环节，该功能损伤可能是导致老年肺组织过度炎症的重要原因。本研究揭示了感染SARS-CoV-2后老年小鼠胞葬作用的特征与功能，为COVID-19的潜在治疗策略提供了重要理论依据。
- SARS-CoV-2
- , 单细胞RNA测序
- , 衰老小鼠
- , 胞葬作用（efferocytosis）
- , 肺泡巨噬细胞
- , 中性粒细胞

Compromised efferocytosis during aging is related to COVID-19 severity in mice

Xianliang Ke ^a,b ,
Xian Lin ^a,b,c ,
Jin Wang ^d ,
Minqi Chen ^e ,
Xiaoqin Jian ^a,b,f ,
Chang Ye ^a,b,f ,
Quanjiao Chen ^a,b,,

a. CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430207, China;
b. Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430207, China;
c. Hubei Jiangxia Laboratory, Wuhan, 430207, China;
d. Department of Endocrinology & Metabolism, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China;
e. Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China;
f. University of Chinese Academy of Sciences, Beijing, 430207, China

Corresponding author: Quanjiao Chen, chenqj@wh.iov.cn
Received Date: 25 January 2025
Accepted Date: 12 May 2025

Abstract

Aging is one of the greatest risk factors for morbidity caused by the coronavirus disease 2019 (COVID-19). In older individuals, a dysregulated immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection contributes to disease severity; however, the underlying mechanism remains elusive. In this study, we established an aging mouse model of COVID-19, successfully replicating the development of a relatively severe disease in older adults. Further single-cell transcriptome analysis revealed a distinct immune cell landscape in the infected lungs, accompanied by an over-activated inflammatory response, especially in aging mice. Compared to young mice, aging mice showed extensive neutrophil activation, NETosis, and a dramatic decrease in the number of alveolar macrophages (AMs). Moreover, as important executors of efferocytosis, AMs exhibited a low efferocytotic gene signature and downregulation of multiple efferocytosis receptors in aged mice. Further analysis indicated that the efferocytosis of neutrophils, whether undergoing apoptosis or NETosis, was compromised after SARS-CoV-2 infection. Since efferocytosis is a key process in inflammatory resolution, impaired efferocytosis may contribute to hyperinflammation in aging lungs. Our study reveals the characteristics and role of efferocytosis in aging mice after SARS-CoV-2 infection and provides valuable insights for the potential treatment of COVID-19.
- SARS-COV-2
- , COVID-19 severity
- , Aging
- , Compromised efferocytosis
- , Alveolar macrophage
- , Neutrophil

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