Single-nucleus transcriptomic profiling of multiple organs in a rhesus macaque model of SARS-CoV-2 infection  

作　　者：Qiang Ma Wenji Ma Tian-Zhang Song Zhaobo Wu Zeyuan Liu Zhenxiang Hu Jian-Bao Han Ling Xu Bo Zeng Bosong Wang Yinuo Sun Dan-Dan Yu Qian Wu Yong-Gang Yao Yong-Tang Zheng Xiaoqun Wang 

机构地区：[1]State Key Laboratory of Brain and Cognitive Science,Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences,KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming,Yunnan 650223,China [4]Kunming National High-Level Biosafety Research Center for Non-Human Primates,Center for Biosafety Mega-Science,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming,Yunnan 650107,China [5]National Resource Center for Non-Human Primates,National Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility),Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming,Yunnan 650107,China [6]LivzonBio,Inc.,Zhuhai,Guangdong 519045,China [7]State Key Laboratory of Cognitive Neuroscience and Learning,Beijing Normal University,Beijing 100875,China [8]IDG/McGovern Institute for Brain Research,Beijing Normal University,Beijing 100875,China [9]Advanced Innovation Center for Human Brain Protection,Beijing Institute for Brain Disorders,Capital Medical University,Beijing 100069,China

出　　处：《Zoological Research》2022年第6期1041-1062,共22页动物学研究（英文）

基　　金：supported by the National Basic Research Program of China(2020YFA0804000,2020YFC0842000,2020YFA0112200,2021YFC2301703);Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32010100);Special Associate Research Program of the Chinese Academy of Sciences(E1290601);National Natural Science Foundation of China(32122037,81891001,32192411,32100512,U1902215);Collaborative Research Fund of the Chinese Institute for Brain Research,Beijing(2020-NKX-PT-03);CAS Project for Young Scientists in Basic Research(YSBR-013);Young Elite Scientist Sponsorship Program by the China Association for Science and Technology(2020QNRC001);National Resource Center for Non-Human Primates;。

摘　　要：Infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs.However, cellular and molecular understanding of SARS-CoV-2 infection-associated pathology and immune defense features in different organs remains incomplete. Here, we profiled approximately 77 000single-nucleus transcriptomes of the lung, liver,kidney, and cerebral cortex in rhesus macaques(Macaca mulatta) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multiorgan dataset suggested that the liver harbored the strongest global transcriptional alterations. We observed prominent impairment in lung epithelial cells, especially in AT2 and ciliated cells, and evident signs of fibrosis in fibroblasts. These lung injury characteristics are similar to those reported in patients with coronavirus disease 2019(COVID-19).Furthermore, we found suppressed MHC class I/II molecular activity in the lung, inflammatory response in the liver, and activation of the kynurenine pathway,which induced the development of an immunosuppressive microenvironment. Analysis of the kidney dataset highlighted tropism of tubule cells to SARS-CoV-2, and we found membranous nephropathy(an autoimmune disease) caused by podocyte dysregulation. In addition, we identified the pathological states of astrocytes and oligodendrocytes in the cerebral cortex, providing molecular insights into COVID-19-related neurological implications. Overall, our multi-organ single-nucleus transcriptomic survey of SARS-CoV-2-infected rhesus macaques broadens our understanding of disease features and antiviral immune defects caused by SARS-CoV-2 infection,which may facilitate the development of therapeutic interventions for COVID-19.

关 键 词：SARS-CoV-2 Rhesus macaque Animal model Single-nucleus RNA sequencing Antiviral immune defects Multiple organs 

分 类 号：R511.9[医药卫生—内科学] R-332[医药卫生—临床医学]