Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia

• Published in: Nature (London) Vol. 590; no. 7847; pp. 635 - 641
• Main Authors: Grant, Rogan A., Morales-Nebreda, Luisa, Markov, Nikolay S., Swaminathan, Suchitra, Querrey, Melissa, Guzman, Estefany R., Abbott, Darryl A., Donnelly, Helen K., Donayre, Alvaro, Goldberg, Isaac A., Klug, Zasu M., Borkowski, Nicole, Lu, Ziyan, Kihshen, Hermon, Politanska, Yuliya, Sichizya, Lango, Kang, Mengjia, Shilatifard, Ali, Qi, Chao, Lomasney, Jon W., Argento, A. Christine, Kruser, Jacqueline M., Malsin, Elizabeth S., Pickens, Chiagozie O., Smith, Sean B., Walter, James M., Pawlowski, Anna E., Schneider, Daniel, Nannapaneni, Prasanth, Abdala-Valencia, Hiam, Bharat, Ankit, Gottardi, Cara J., Budinger, G. R. Scott, Misharin, Alexander V., Singer, Benjamin D., Wunderink, Richard G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.02.2021; Nature Publishing Group
• Subjects: 13/21; 13/51; 14/32; 38; 38/91; 49/31; 631/250/255/2514; 631/326/596/4130; 692/699/255/2514; Alveoli; Alveolitis; Analysis; Bacterial pneumonia; Bronchoalveolar Lavage Fluid - chemistry; Bronchoalveolar Lavage Fluid - immunology; Bronchus; Causes of; Cell activation; Chemokines; Chemotactic factors; Cohort Studies; Complications and side effects; Coronaviridae; Coronaviruses; COVID-19; COVID-19 - genetics; COVID-19 - immunology; COVID-19 - virology; Cytokines; Feedback loops; Flow cytometry; Gene sequencing; Genes; Humanities and Social Sciences; Humans; Immune response; Immune system; Inflammation; Interferon; Interferon-gamma - immunology; Interferons - immunology; Interferons - metabolism; Intubation; Lavage; Lymphocytes; Lymphocytes T; Macrophages; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Macrophages, Alveolar - virology; Monocytes; Mortality; multidisciplinary; Neutrophils; Pandemics; Pathogens; Physiological aspects; Pneumonia; Pneumonia, Viral - genetics; Pneumonia, Viral - immunology; Pneumonia, Viral - virology; Positive feedback; Respiratory diseases; Respiratory failure; Ribonucleic acid; RNA; RNA-Seq; SARS-CoV-2 - immunology; SARS-CoV-2 - pathogenicity; Science; Science (multidisciplinary); Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Signal Transduction - immunology; Single-Cell Analysis; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Time Factors; Transcriptomics; Ventilators; Viral diseases; Viruses; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-020-03148-w

Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome 1 (ARDS). Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from that in other types of pneumonia 2 . Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation. Analysis of bronchoalveolar lavage fluid samples from patients with SARS-CoV-2-induced respiratory failure suggests that SARS-CoV-2 infects alveolar macrophages to cause release of T cell chemoattractants, thereby inducing local inflammatory cytokine release and further T cell activation, ultimately resulting in a positive feedback loop that drives alveolar inflammation.