Distinct lung cell signatures define the temporal evolution of diffuse alveolar damage in fatal COVID-19

Abstract

Background: Lung damage in severe COVID-19 is highly heterogeneous however studies with dedicated spatial distinction of discrete temporal phases of diffuse alveolar damage (DAD) and alternate lung injury patterns are lacking. Existing studies have also not accounted for progressive airspace obliteration in cellularity estimates. We used an imaging mass cytometry (IMC) analysis with a novel airspace correction step to more accurately identify the cellular immune response that underpins the heterogeneity of severe COVID-19 lung disease. Methods: Lung tissue was obtained at post-mortem from severe COVID-19 deaths. Pathologist-selected regions of interest (ROIs) were chosen by light microscopy representing the patho-evolutionary spectrum of DAD and alternate disease phenotypes were selected for comparison. Architecturally normal SARS-CoV-2-positive lung tissue and tissue from SARS-CoV-2-negative donors served as controls. ROIs were stained for 40 cellular protein markers and ablated using IMC before segmented cells were classified. Cell populations corrected by ROI airspace and their spatial relationships were compared across lung injury patterns. Results: Forty patients (32M:8F, age:22-98), 345 ROIs and >900k single cells were analysed. DAD progression was marked by airspace obliteration and significant increases in mononuclear phagocytes (MnPs), T and B lymphocytes and significant decreases in alveolar epithelial and endothelial cells. Neutrophil populations proved stable overall although several interferon-responding subsets demonstrated expansion. Spatial analysis revealed immune cell interactions occur prior to microscopically appreciable tissue injury. Conclusions: The immunopathogenesis of severe DAD in COVID-19 lung disease is characterised by sustained increases in MnPs and lymphocytes with key interactions occurring even prior to lung injury is established.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work was partly funded by UKRI/Medical Research Council through the UK Coronavirus Immunology Consortium (UK-CIC) as well as the Barbour Foundation. L Milross was supported by a General Sir John Monash Scholarship awarded by the General Sir John Monash Foundation and a Vice-Chancellors Global Scholarship from Newcastle University in support of a Master of Research in Immunobiology at Newcastle University. A Thomspon was supported by funding from the JGW Patterson Foundation. C. J. A. Duncan was supported by a Wellcome Clinical Research Career Development Fellowship (211153/Z/18/Z).

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Ethics committee of North East - Newcastle & North Tyneside 1 Research gave ethical approval for this work. Ethics committee of the Wales Research Ethics Committee 3 gave ethical approval for this work. Ethics committee of the East of Scotland Research Ethics Service gave ethical approval for this work.

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Data Availability

All data produced in the present study are available upon reasonable request to the authors

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