Crucial role played by CK8<sup>+</sup> cells in mediating alveolar injury remodeling for patients with COVID-19

Yufeng Li; Hengrui Hu; Jia Liu; Longda Ma; Xi Wang; Liang Liu; Qian Liu; Liang Ren; Jiang Li; Fei Deng; Zhihong Hu; Yiwu Zhou; Manli Wang

doi:10.1016/j.virs.2024.03.007

June 2024

Yufeng Li, Hengrui Hu, Jia Liu, Longda Ma, Xi Wang, Liang Liu, Qian Liu, Liang Ren, Jiang Li, Fei Deng, Zhihong Hu, Yiwu Zhou and Manli Wang. Crucial role played by CK8+ cells in mediating alveolar injury remodeling for patients with COVID-19[J]. Virologica Sinica, 2024, 39(3): 390-402. doi: 10.1016/j.virs.2024.03.007

Citation: Yufeng Li, Hengrui Hu, Jia Liu, Longda Ma, Xi Wang, Liang Liu, Qian Liu, Liang Ren, Jiang Li, Fei Deng, Zhihong Hu, Yiwu Zhou, Manli Wang. Crucial role played by CK8⁺ cells in mediating alveolar injury remodeling for patients with COVID-19 .VIROLOGICA SINICA, 2024, 39(3) : 390-402. http://dx.doi.org/10.1016/j.virs.2024.03.007

CK8+细胞在介导新冠肺炎患者肺泡损伤-重建中的关键作用

李玉凤 ^a,c ,
胡恒睿 ^a ,
刘佳 ^a ,
马龙达 ^b ,
汪习 ^a ,
刘良 ^b ,
刘茜 ^b ,
任亮 ^b ,
李江 ^a ,
邓菲 ^a ,
胡志红 ^a ,
周亦武 ^b,, ,
王曼丽 ^a,,

cstr: 32224.14.j.virs.2024.03.007

a. 中国科学院武汉病毒研究所;
b. 华中科技大学同济医学院;
c. 中国科学院大学

通讯作者： 周亦武, zhouyiwu@hust.edu.cn; 王曼丽, wangml@wh.iov.cn
收稿日期： 2023-12-01
录用日期： 2024-03-18

摘要

SARS-CoV-2感染和再次感染的高风险以及急性感染后肺部后遗症的发生，提示了解SARS-CoV-2感染后肺部损伤及修复机制的重要性。为了对SARS-CoV-2感染引起的肺部损伤修复机制进行探究，我们对新冠肺炎患者和SARS-CoV-2感染的动物模型进行了肺部病理的系统分析。研究结果显示在9名新冠肺炎死亡患者和1名新冠肺炎康复患者的肺部，表达CK8标志物的损伤相关瞬时祖细胞（DATP）显著增生。对CK8+DATP细胞可能的来源进行探究，结果显示CK8+DATP细胞来源于支气管CK5+基底细胞。然而在死亡和康复患者中，CK8+DATP细胞表现出向I型肺泡上皮细胞（AT I）分化的不同细胞命运，康复患者肺部CK8+DATP细胞可成功分化为AT I细胞，但是在死亡患者肺部CK8+DATP细胞几乎不能分化为AT I细胞。通过使用模拟轻度新冠肺炎患者肺部损伤重塑动态过程的自限性地鼠感染模型，发现CK8+DATP细胞的积累和消退与疾病进程密切相关。我们也对两名在2022年底/2023年初死于Omicron株的感染患者肺部进行了病理分析，死者肺部病理仅表现出轻微的病理损伤，且没有CK8+DATP细胞增生。结果明确了肺细胞重塑途径，并表明CK8+DATP细胞在介导肺泡重塑中发挥主要作用，提示CK8+DATP细胞是作为诊断标志物和治疗靶点的潜在应用。
- 新型冠状病毒
- , CK8+DATP细胞
- , 细胞增生
- , 肺损伤重塑
- , 尸检
- , 仓鼠感染模型

Crucial role played by CK8⁺ cells in mediating alveolar injury remodeling for patients with COVID-19

Yufeng Li ^a,c ,
Hengrui Hu ^a ,
Jia Liu ^a ,
Longda Ma ^b ,
Xi Wang ^a ,
Liang Liu ^b ,
Qian Liu ^b ,
Liang Ren ^b ,
Jiang Li ^a ,
Fei Deng ^a ,
Zhihong Hu ^a ,
Yiwu Zhou ^b,, ,
Manli Wang ^a,,

a. State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China;
b. Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430010, China;
c. University of the Chinese Academy of Sciences, Beijing, 100049, China

Corresponding author: Yiwu Zhou, zhouyiwu@hust.edu.cn Manli Wang, wangml@wh.iov.cn
Received Date: 01 December 2023
Accepted Date: 18 March 2024

Abstract

The high risk of SARS-CoV-2 infection and reinfection and the occurrence of post-acute pulmonary sequelae have highlighted the importance of understanding the mechanism underlying lung repair after injury. To address this concern, comparative and systematic analyses of SARS-CoV-2 infection in COVID-19 patients and animals were conducted. In the lungs of nine patients who died of COVID-19 and one recovered from COVID-19 but died of unrelated disease in early 2020, damage-related transient progenitor (DATP) cells expressing CK8 marker proliferated significantly. These CK8+ DATP cells were derived from bronchial CK5+ basal cells. However, they showed different cell fate toward differentiation into type I alveolar cells in the deceased and convalescent patients, respectively. By using a self-limiting hamster infection model mimicking the dynamic process of lung injury remodeling in mild COVID-19 patients, the accumulation and regression of CK8+ cell marker were found to be closely associated with the disease course. Finally, we examined the autopsied lungs of two patients who died of infection by the recent Omicron variant and found that they only exhibited mild pathological injury with no CK8+ cell proliferation. These results indicate a clear pulmonary cell remodeling route and suggest that CK8+ DATP cells play a primary role in mediating alveolar remodeling, highlighting their potential applications as diagnostic markers and therapeutic targets.
- SARS-CoV-2
- , CK8⁺ DATP cells
- , Cell proliferation
- , Lung injury-remodeling
- , Autopsy
- , Hamster infection model

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