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

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 ( 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.

Comparative transcriptome analysis between rhesus macaques (<i>Macaca mulatta</i>) and crab-eating macaques (<i>M. fascicularis</i>)

“…The primate genus Macaca , belonging to the Old World monkeys, is of notable importance due to its wide geographic distribution and strong adaptability ( Fan et al, 2017 ; Shao et al, 2023 ). Rhesus macaques ( M. mulatta , MMU) and crab-eating macaques ( M. fascicularis , MFA) are two extensively utilized non-human primate (NHP) models in biomedical research ( Juan et al, 2023 ; Lan et al, 2020 ; Ma et al, 2022 ; Zhang et al, 2020 ). Nonetheless, prior comparative transcriptomic studies on these macaques have been confined to a limited number of tissues ( Blake et al, 2020 ; Yan et al, 2011 ), thus restricting our understanding of the gene expression patterns within and between these two species.…”

COVID‐19‐associated liver injury: Adding fuel to the flame

“…Single-nucleus transcriptomic profiling of multiple organs depicted that the increased expressions of TDO2 and IDO2 in hepatocytes after SARS-CoV-2 infected in a rhesus macaque model. 148 Tryptophan is mainly metabolized by TDO in the liver under physiological conditions, while it is metabolized by IDO related to inflammatory responses after damage. Proinflammatory cytokines convert tryptophan to kynurenine, which is associated with IL-6 peaks during acute SARS-CoV-2 infection.…”

“…Tryptophan deficiency in COVID‐19 patients predicts altered indoleamine‐2,3‐dioxygenase (IDO) and tryptophan 2,3‐dioxygenase (TDO) enzyme activity, and probably concomitant with kynurenine pathway activation. Single‐nucleus transcriptomic profiling of multiple organs depicted that the increased expressions of TDO2 and IDO2 in hepatocytes after SARS‐CoV‐2 infected in a rhesus macaque model 148 . Tryptophan is mainly metabolized by TDO in the liver under physiological conditions, while it is metabolized by IDO related to inflammatory responses after damage.…”

Ferrets: A powerful model of SARS-CoV-2

“…Establishing an ideal animal model for COVID-19 is of great significance for clarifying the pathogenic mechanisms of disease and testing the efficacy of vaccines and antiviral agents. To date, mice, hamsters, ferrets, minks, tree shrews, and several non-human primates (NHPs) have been used to study SARS-CoV-2 infection ( Ma et al, 2022 ; Xu et al, 2020 ). Among them, ferrets are naturally susceptible to SARS-CoV-2 and have been widely used in respiratory virus research ( Kim et al, 2020 ; Wong et al, 2019 ).…”