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Nature
02, 2021;590 (7847): 635-641.

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

Rogan A Grant, Luisa Morales-Nebreda, Nikolay S Markov, Suchitra Swaminathan, Melissa Querrey, Estefany R Guzman, Darryl A Abbott, Helen K Donnelly, Alvaro Donayre, Isaac A Goldberg, Zasu M Klug, Nicole Borkowski, Ziyan Lu, Hermon Kihshen, Yuliya Politanska, Lango Sichizya, Mengjia Kang, Ali Shilatifard, Chao Qi, Jon W Lomasney, A Christine Argento, Jacqueline M Kruser, Elizabeth S Malsin, Chiagozie O Pickens, Sean B Smith, James M Walter, Anna E Pawlowski, Daniel Schneider, Prasanth Nannapaneni, Hiam Abdala-Valencia, Ankit Bharat, Cara J Gottardi, G R Scott Budinger, Alexander V Misharin, Benjamin D Singer, Richard G Wunderink, NU SCRIPT Study Investigators
Author Information
  1. Rogan A Grant: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. ORCID
  2. Luisa Morales-Nebreda: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  3. Nikolay S Markov: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. ORCID
  4. Suchitra Swaminathan: Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  5. Melissa Querrey: Division of Thoracic Surgery, Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  6. Estefany R Guzman: Robert H. Lurie Comprehensive Cancer Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  7. Darryl A Abbott: Robert H. Lurie Comprehensive Cancer Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  8. Helen K Donnelly: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  9. Alvaro Donayre: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  10. Isaac A Goldberg: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. ORCID
  11. Zasu M Klug: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  12. Nicole Borkowski: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  13. Ziyan Lu: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  14. Hermon Kihshen: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  15. Yuliya Politanska: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  16. Lango Sichizya: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  17. Mengjia Kang: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  18. Ali Shilatifard: Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. ORCID
  19. Chao Qi: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  20. Jon W Lomasney: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. ORCID
  21. A Christine Argento: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  22. Jacqueline M Kruser: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  23. Elizabeth S Malsin: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  24. Chiagozie O Pickens: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  25. Sean B Smith: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  26. James M Walter: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  27. Anna E Pawlowski: Clinical and Translational Sciences Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  28. Daniel Schneider: Clinical and Translational Sciences Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. ORCID
  29. Prasanth Nannapaneni: Clinical and Translational Sciences Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  30. Hiam Abdala-Valencia: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  31. Ankit Bharat: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  32. Cara J Gottardi: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  33. G R Scott Budinger: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. s-buding@northwestern.edu. ORCID
  34. Alexander V Misharin: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. a-misharin@northwestern.edu. ORCID
  35. Benjamin D Singer: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. benjamin-singer@northwestern.edu. ORCID
  36. Richard G Wunderink: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. r-wunderink@northwestern.edu. ORCID
PMID: 33429418 DOI: 10.1038/s41586-020-03148-w

Abstract

Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome (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. 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.

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Grants

  1. I01 CX001777/CSRD VA
  2. HL147290/NIH HHS
  3. R01 HL131745/NHLBI NIH HHS
  4. S10 OD011996/NIH HHS
  5. P01 AG049665/NIA NIH HHS
  6. U19 AI135964/NIAID NIH HHS
  7. P30 CA060553/NCI NIH HHS
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  10. R01 HL147575/NHLBI NIH HHS
  11. R56 HL135124/NHLBI NIH HHS
  12. R01 HL134800/NHLBI NIH HHS
  13. GM129312/NIH HHS
  14. HL134800/NIH HHS
  15. K08 HL159356/NHLBI NIH HHS
  16. L30 CA153420/NCI NIH HHS
  17. K08 HL128867/NHLBI NIH HHS
  18. 1S10OD011996-01/NIH HHS
  19. R01 HL153312/NHLBI NIH HHS
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  26. R01 HL154686/NHLBI NIH HHS
  27. R01 GM129312/NIGMS NIH HHS
  28. F31 AG071225/NIA NIH HHS
  29. R01 HL149883/NHLBI NIH HHS
  30. K07 CA216330/NCI NIH HHS
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MeSH Term

Bronchoalveolar Lavage Fluid
COVID-19
Cohort Studies
Humans
Interferon-gamma
Interferons
Macrophages, Alveolar
Pneumonia, Viral
RNA-Seq
SARS-CoV-2
Signal Transduction
Single-Cell Analysis
T-Lymphocytes
Time Factors

Chemicals

Interferon-gamma
Interferons
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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