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

Luke Milross Orcid Logo, Bethany Hunter, David McDonald, George Merces, Amanda Thomson, Catharien M.U. Hilkens, John Wills, Paul Rees Orcid Logo, Kasim Jiwa, Nigel Cooper, Joaquim Majo, Helen Ashwin, Christopher J.A. Duncan, Paul M. Kaye, Omer Ali Bayraktar, Andrew Filby, Andrew J. Fisher

eBioMedicine, Volume: 99, Start page: 104945

Swansea University Author: Paul Rees Orcid Logo

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DOI (Published version): 10.1016/j.ebiom.2023.104945

Abstract

BackgroundLung 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 obliterat...

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Published in: eBioMedicine
ISSN: 2352-3964
Published: Elsevier BV 2024
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We used an imaging mass cytometry (IMC) analysis with an airspace correction step to more accurately identify the cellular immune response that underpins the heterogeneity of severe COVID-19 lung disease.MethodsLung 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.FindingsForty patients (32M:8F, age: 22&#x2013;98), 345 ROIs and &gt;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.InterpretationThe 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.</abstract><type>Journal Article</type><journal>eBioMedicine</journal><volume>99</volume><journalNumber/><paginationStart>104945</paginationStart><paginationEnd/><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>2352-3964</issnPrint><issnElectronic/><keywords>COVID-19; Post-mortem lung tissue; Diffuse alveolar damage; Immunopathology; Imaging mass cytometry</keywords><publishedDay>1</publishedDay><publishedMonth>1</publishedMonth><publishedYear>2024</publishedYear><publishedDate>2024-01-01</publishedDate><doi>10.1016/j.ebiom.2023.104945</doi><url/><notes/><college>COLLEGE NANME</college><department>Engineering and Applied Sciences School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>EAAS</DepartmentCode><institution>Swansea University</institution><apcterm>External research funder(s) paid the OA fee (includes OA grants disbursed by the Library)</apcterm><funders>This work was partly funded by UKRI/Medical Research Council through the UK Coronavirus Immunology Consortium (UK-CIC) as well as the Barbour Foundation.</funders><projectreference/><lastEdited>2025-01-16T12:20:19.8015446</lastEdited><Created>2024-11-06T19:31:52.0166483</Created><path><level id="1">Faculty of Science and Engineering</level><level id="2">School of Engineering and Applied Sciences - Biomedical Engineering</level></path><authors><author><firstname>Luke</firstname><surname>Milross</surname><orcid>0000-0002-6268-1652</orcid><order>1</order></author><author><firstname>Bethany</firstname><surname>Hunter</surname><order>2</order></author><author><firstname>David</firstname><surname>McDonald</surname><order>3</order></author><author><firstname>George</firstname><surname>Merces</surname><order>4</order></author><author><firstname>Amanda</firstname><surname>Thomson</surname><order>5</order></author><author><firstname>Catharien M.U.</firstname><surname>Hilkens</surname><order>6</order></author><author><firstname>John</firstname><surname>Wills</surname><order>7</order></author><author><firstname>Paul</firstname><surname>Rees</surname><orcid>0000-0002-7715-6914</orcid><order>8</order></author><author><firstname>Kasim</firstname><surname>Jiwa</surname><order>9</order></author><author><firstname>Nigel</firstname><surname>Cooper</surname><order>10</order></author><author><firstname>Joaquim</firstname><surname>Majo</surname><order>11</order></author><author><firstname>Helen</firstname><surname>Ashwin</surname><order>12</order></author><author><firstname>Christopher J.A.</firstname><surname>Duncan</surname><order>13</order></author><author><firstname>Paul M.</firstname><surname>Kaye</surname><order>14</order></author><author><firstname>Omer Ali</firstname><surname>Bayraktar</surname><order>15</order></author><author><firstname>Andrew</firstname><surname>Filby</surname><order>16</order></author><author><firstname>Andrew J.</firstname><surname>Fisher</surname><order>17</order></author></authors><documents><document><filename>68201__33355__cdde0c9b5ee443ffa1711fd796f7adfa.pdf</filename><originalFilename>68201.VoR.pdf</originalFilename><uploaded>2025-01-16T12:18:21.8087361</uploaded><type>Output</type><contentLength>4371098</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>&#xA9; 2023 The Author(s). 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spelling 2025-01-16T12:20:19.8015446 v2 68201 2024-11-06 Distinct lung cell signatures define the temporal evolution of diffuse alveolar damage in fatal COVID-19 537a2fe031a796a3bde99679ee8c24f5 0000-0002-7715-6914 Paul Rees Paul Rees true false 2024-11-06 EAAS BackgroundLung 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 an airspace correction step to more accurately identify the cellular immune response that underpins the heterogeneity of severe COVID-19 lung disease.MethodsLung 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.FindingsForty 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.InterpretationThe 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. Journal Article eBioMedicine 99 104945 Elsevier BV 2352-3964 COVID-19; Post-mortem lung tissue; Diffuse alveolar damage; Immunopathology; Imaging mass cytometry 1 1 2024 2024-01-01 10.1016/j.ebiom.2023.104945 COLLEGE NANME Engineering and Applied Sciences School COLLEGE CODE EAAS Swansea University External research funder(s) paid the OA fee (includes OA grants disbursed by the Library) This work was partly funded by UKRI/Medical Research Council through the UK Coronavirus Immunology Consortium (UK-CIC) as well as the Barbour Foundation. 2025-01-16T12:20:19.8015446 2024-11-06T19:31:52.0166483 Faculty of Science and Engineering School of Engineering and Applied Sciences - Biomedical Engineering Luke Milross 0000-0002-6268-1652 1 Bethany Hunter 2 David McDonald 3 George Merces 4 Amanda Thomson 5 Catharien M.U. Hilkens 6 John Wills 7 Paul Rees 0000-0002-7715-6914 8 Kasim Jiwa 9 Nigel Cooper 10 Joaquim Majo 11 Helen Ashwin 12 Christopher J.A. Duncan 13 Paul M. Kaye 14 Omer Ali Bayraktar 15 Andrew Filby 16 Andrew J. Fisher 17 68201__33355__cdde0c9b5ee443ffa1711fd796f7adfa.pdf 68201.VoR.pdf 2025-01-16T12:18:21.8087361 Output 4371098 application/pdf Version of Record true © 2023 The Author(s). This is an open access article under the CC BY license. true eng http://creativecommons.org/licenses/by/4.0/
title Distinct lung cell signatures define the temporal evolution of diffuse alveolar damage in fatal COVID-19
spellingShingle Distinct lung cell signatures define the temporal evolution of diffuse alveolar damage in fatal COVID-19
Paul Rees
title_short Distinct lung cell signatures define the temporal evolution of diffuse alveolar damage in fatal COVID-19
title_full Distinct lung cell signatures define the temporal evolution of diffuse alveolar damage in fatal COVID-19
title_fullStr Distinct lung cell signatures define the temporal evolution of diffuse alveolar damage in fatal COVID-19
title_full_unstemmed Distinct lung cell signatures define the temporal evolution of diffuse alveolar damage in fatal COVID-19
title_sort Distinct lung cell signatures define the temporal evolution of diffuse alveolar damage in fatal COVID-19
author_id_str_mv 537a2fe031a796a3bde99679ee8c24f5
author_id_fullname_str_mv 537a2fe031a796a3bde99679ee8c24f5_***_Paul Rees
author Paul Rees
author2 Luke Milross
Bethany Hunter
David McDonald
George Merces
Amanda Thomson
Catharien M.U. Hilkens
John Wills
Paul Rees
Kasim Jiwa
Nigel Cooper
Joaquim Majo
Helen Ashwin
Christopher J.A. Duncan
Paul M. Kaye
Omer Ali Bayraktar
Andrew Filby
Andrew J. Fisher
format Journal article
container_title eBioMedicine
container_volume 99
container_start_page 104945
publishDate 2024
institution Swansea University
issn 2352-3964
doi_str_mv 10.1016/j.ebiom.2023.104945
publisher Elsevier BV
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Biomedical Engineering{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Biomedical Engineering
document_store_str 1
active_str 0
description BackgroundLung 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 an airspace correction step to more accurately identify the cellular immune response that underpins the heterogeneity of severe COVID-19 lung disease.MethodsLung 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.FindingsForty 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.InterpretationThe 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.
published_date 2024-01-01T05:23:41Z
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