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

Abstract

Some patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) develop severe pneumonia and the acute respiratory distress syndrome (ARDS)1. 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 other types of pneumonia2. 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 subjected them to flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA-seq on 10 bronchoalveolar lavage fluid samples collected from patients with severe COVID-19 within 48 hours 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-gamma 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 harboring SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.

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Correspondence to G. R. Scott Budinger or Alexander V. Misharin or Benjamin D. Singer or Richard G. Wunderink.

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Reporting Summary

Supplemental Data File 1

Data related to k-means clustering and differential expression analysis (DEA) of bulk RNA-seq samples: gene cluster assignments, cluster GO enrichment, pairwise DEA across diagnosis, and WGCNA module assignments. Excel workbook, multiple tabs.

Supplemental Data File 2

Raw bulk RNA-seq gene counts. CSV file.

Supplemental Data File 3

Bulk RNA-seq metadata. CSV file.

Supplemental Data File 4

Marker genes for integrated scRNA-seq object containing cells from 10 patients with COVID-19. CSV file.

Supplemental Data File 5

Marker genes for integrated scRNA-seq object containing cells from 10 patients with COVID-19, one patient with bacterial pneumonia and one intubated non-pneumonia control. CSV file.

Supplemental Data File 6

Differentially expressed genes between TRAM1 and TRAM2 clusters. CSV file.

Supplemental Data File 7

SARS-CoV-2 infection is spatially restricted. Combined immunofluorescence microscopy for CD206, a marker of mature macrophages (red), and smFISH (RNAscope) for positive- (yellow) and negative-strand (cyan) SARS-CoV-2 transcripts.

Supplemental Data File 8

Standardized tool for pneumonia category adjudication.

Supplemental Data File 9

Cell-type percentages from flow cytometry analysis, including metadata for flow cytometry, bulk RNA-seq, and single-cell RNA-seq data.

Supplemental Data Video 1

Detection of SARS-CoV-2 positive and negative strand transcripts in a CD206-positive alveolar macrophage. Combined immunofluorescence microscopy for CD206, a marker of mature macrophages (red), and smFISH (RNAscope) for positive- (yellow) and negative-strand (cyan) SARS-CoV-2 transcripts.

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Grant, R.A., Morales-Nebreda, L., Markov, N.S. et al. Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia. Nature (2021). https://doi.org/10.1038/s41586-020-03148-w

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