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

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 ( Macaca mulatta) 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.新型冠状病毒（SARS-CoV-2）感染可以造成多种临床表现和多种器官的组织损伤。但是对于新冠病毒感染相关的病理和免疫防御特征的细胞和分子水平的理解还不完善。该研究中，我们对感染新冠病毒的猕猴及健康对照个体的肺脏、肝脏、肾脏、大脑皮层进行单细胞核转录组测序和分析，共获得了约77 000个单细胞核的转录组数据。多器官数据集整合分析结果表明肝脏具有最强的全局转录改变。我们发现肺脏中的上皮细胞，尤其是AT2细胞和纤毛细胞，存在突出的损伤特征，在成纤维细胞中纤维化迹象明显。肺部的这些损伤特征与新冠肺炎（COVID-19）病人中报道的结果很相似。此外，我们发现肺中的主要组织相容性复合体（MHC）I/II类分子活性下调，肝脏中存在炎症反应和犬尿氨酸通路的激活，它会诱导免疫抑制性微环境的发展。对肾脏数据集的分析发现肾小管上皮细胞对新冠病毒具有更强的趋向性，同时发现了感染猕猴出现了由足细胞失调引起的膜性肾病(一种自身免疫疾病)。另外，我们还识别到了大脑皮层中星形胶质细胞和少突胶质细胞的病理状态，为新冠肺炎相关的神经学影响提供了分子洞察。总之，此项对新冠病毒感染的猕猴模型多器官进行单细胞核转录组研究的工作拓宽了我们对新冠病毒感染造成的疾病特征和机体抗病毒免疫缺陷的理解，这可能促进新冠肺炎治疗干预手段的开发。.