Ke Xianliang, Lin Xian, Wang Jin, Chen Minqi, Jian Xiaoqin, Ye Chang, Chen Quanjiao
CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430207, China; Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430207, China.
CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430207, China; Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430207, China; Hubei Jiangxia Laboratory, Wuhan, 430207, China.
Virol Sin. 2025 Jun;40(3):419-429. doi: 10.1016/j.virs.2025.05.008. Epub 2025 May 24.
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.
衰老 是 2019 冠状病毒病（COVID - 19）所致发病的最大风险因素之一。在老年个体中，对严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染的免疫反应失调会导致疾病严重程度增加；然而，其潜在机制仍不清楚。在本研究中，我们建立了 COVID - 19 衰老小鼠模型，成功复制了老年成年人中相对严重疾病的发展过程。进一步的单细胞转录组分析揭示了受感染肺组织中独特的免疫细胞格局，伴随着过度激活的炎症反应，尤其是在衰老小鼠中。与年轻小鼠相比，衰老小鼠表现出广泛的中性粒细胞激活、中性粒细胞胞外陷阱形成（NETosis），以及肺泡巨噬细胞（AM）数量的显著减少。此外，作为吞噬作用的重要执行者，老年小鼠的 AM 表现出低吞噬基因特征以及多种吞噬作用受体的下调。进一步分析表明，SARS-CoV-2 感染后，无论是经历凋亡还是 NETosis 的中性粒细胞的吞噬作用均受损。由于吞噬作用是炎症消退的关键过程，受损的吞噬作用可能导致衰老肺组织中的炎症加剧。我们的研究揭示了 SARS-CoV-2 感染后衰老小鼠吞噬作用的特征和作用，并为 COVID - 19 的潜在治疗提供了有价值的见解。
