Single-nucleus transcriptomic profiling of multiple organs in a rhesus macaque model of SARS-CoV-2 infection
Qiang Ma, 中国科学院生物物理研究所脑与认知科学国家重点实验室, 北京100101, 中国, Wenji Ma, Tian‐Zhang Song, Zhaobo Wu, Zeyuan Liu, Zhenxiang Hu, Jian-Bao Han, Ling Xu, Bo Zeng, Bosong Wang, Yinuo Sun, Dandan Yu, Qian Wu, Yong‐Gang Yao, Yong‐Tang Zheng, Xiaoqun Wang, 中国科学院大学, 北京100049, 中国, 中国科学院昆明动物研究所动物模型与人类疾病机理重点实验室, KIZ-CUHK生物资源与疾病分子机理联合实验室, 云南 昆明 650223, 中国, 中国科学院昆明动物研究所昆明国家高等级生物安全灵长类动物实验中心, 生物安全大科学研究中心, 云南 昆明 650107, 中国, 中国科学院昆明动物研究所模式动物表型与遗传研究国家重大科技基础设施(灵长类动物设施), 国家非人灵长类实验动物资源库, 云南 昆明 650107, 中国, 珠海市丽珠生物医药科技有限公司, 广东 珠海 519045, 中国, 北京师范大学认知神经科学与学习国家重点实验室, 北京100875, 中国, 北京师范大学IDG麦戈文脑科学研究所, 北京100875, 中国, 首都医科大学北京脑重大疾病研究院, 人脑保护高精尖创新中心, 北京100069, 中国
Abstract
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 77 000 single-nucleus transcriptomes of the lung, liver, kidney, and cerebral cortex in rhesus macaques (<i>Macaca mulatta</i>) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multi-organ 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.