Single-cell RNA sequencing of lungs of SARS-CoV-2–infected African green monkeys reveals virus replication and host response dynamics in vivo. A dynamic response to SARS-CoV-2 While a number of animal models for SARS-CoV-2 have been developed, nonhuman primates are among the best at recapitulating human COVID-19. Here, Speranza et al . used single-cell RNA sequencing to demonstrate that SARS-CoV-2 replicates in the lung of African green monkeys and that immune cell populations in the lung change over the course of infection. Sequencing data revealed that pneumocytes are the site of viral replication in the lung, and infiltrating macrophages are responsible for clearing infected cells and cellular debris early in infection. Together, these findings further our understanding of the dynamics of SARS-CoV-2 infection and host immune responses in vivo. Detailed knowledge about the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is important for uncovering the viral and host factors that contribute to coronavirus disease 2019 (COVID-19) pathogenesis. Old-World nonhuman primates recapitulate mild to moderate cases of COVID-19, thereby serving as important pathogenesis models. We compared African green monkeys inoculated with infectious SARS-CoV-2 or irradiated, inactivated virus to study the dynamics of virus replication throughout the respiratory tract. Genomic RNA from the animals inoculated with the irradiated virus was found to be highly stable, whereas subgenomic RNA, an indicator of viral replication, was found to degrade quickly. We combined this information with single-cell RNA sequencing of cells isolated from the lung and lung-draining mediastinal lymph nodes and developed new analysis methods for unbiased targeting of important cells in the host response to SARS-CoV-2 infection. Through detection of reads to the viral genome, we were able to determine that replication of the virus in the lungs appeared to occur mainly in pneumocytes, whereas macrophages drove the inflammatory response. Monocyte-derived macrophages recruited to the lungs, rather than tissue-resident alveolar macrophages, were most likely to be responsible for phagocytosis of infected cells and cellular debris early in infection, with their roles switching during clearance of infection. Together, our dataset provides a detailed view of the dynamics of virus replication and host responses over the course of mild COVID-19 and serves as a valuable resource to identify therapeutic targets.
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