Abstract

Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyze the transcriptomes of 611,398 single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in patients with chronic lung diseases. We observe a similar cellular distribution and relative expression of SARS-CoV-2 entry factors in control and CLD lungs. CLD AT2 cells express higher levels of genes linked directly to the efficiency of viral replication and the innate immune response. Additionally, we identify basal differences in inflammatory gene expression programs that highlight how CLD alters the inflammatory microenvironment encountered upon viral exposure to the peripheral lung. Our study indicates that CLD is accompanied by changes in cell-type-specific gene expression programs that prime the lung epithelium for and influence the innate and adaptive immune responses to SARS-CoV-2 infection.

Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 and poor outcomes. Here the authors compare the transcriptomes of single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in these patients.

Details

Title
Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity
Author
Bui, Linh T 1   VIAFID ORCID Logo  ; Winters, Nichelle I 2 ; Mei-I, Chung 1 ; Chitra, Joseph 3   VIAFID ORCID Logo  ; Gutierrez, Austin J 1   VIAFID ORCID Logo  ; Habermann, Arun C 2 ; Adams, Taylor S 4 ; Schupp, Jonas C 4   VIAFID ORCID Logo  ; Poli, Sergio 5   VIAFID ORCID Logo  ; Peter, Lance M 1 ; Taylor, Chase J 2 ; Blackburn, Jessica B 2 ; Richmond, Bradley W 6   VIAFID ORCID Logo  ; Nicholson, Andrew G 7 ; Rassl Doris 8 ; Wallace, William A 9   VIAFID ORCID Logo  ; Rosas, Ivan O 10 ; Gisli, Jenkins R 3   VIAFID ORCID Logo  ; Kaminski Naftali 4   VIAFID ORCID Logo  ; Kropski, Jonathan A 11 ; Banovich, Nicholas E 1 ; Misharin Alexander V 12 ; Tsankov, Alexander M 13 ; Spira Avrum 14 ; Barbry Pascal 15 ; Alvis, Brazma 16 ; Samakovlis Christos 17 ; Shepherd, Douglas P 18 ; Rawlins, Emma L 19 ; Theis, Fabian J 20 ; Griffonnet, Jennifer 21 ; Lee, Haeock 22 ; Schiller, Herbert B 23 ; Hofman, Paul 24 ; Powell, Joseph E 25 ; Schultze, Joachim L 26 ; Whitsett, Jeffrey 27 ; Choi, Jiyeon 28 ; Lundeberg Joakim 29 ; Ordovas-Montanes Jose 30 ; Jayaraj, Rajagopal 31 ; Meyer, Kerstin B 32 ; Krasnow, Mark A 33 ; Saeb‐Parsy Kourosh 34 ; Zhang, Kun 35 ; Lafyatis, Robert 36 ; Leroy, Sylvie 37 ; Haniffa Muzlifah 38 ; Nawijn, Martijn C 39 ; Nikolić, Marko Z 40 ; van den Berge Maarten 41 ; Kuhnemund Malte 42 ; Charles-Hugo, Marquette 43 ; Von Papen Michael 44 ; Eickelberg Oliver 45 ; Rosenblatt-Rosen, Orit 46 ; Reyfman, Paul A 47 ; Pe’er Dana 48 ; Horvath, Peter 49 ; Tata Purushothama Rao 50 ; Regev Aviv 51 ; Rojas, Mauricio 52 ; Seibold, Max A 53 ; Shalek, Alex K 54 ; Spence, Jason R 55 ; Teichmann, Sarah A 56 ; Quake, Stephen 57 ; Duong, Thu Elizabeth 58 ; Biancalani Tommaso 59 ; Desai Tushar 60 ; Sun, Xin 61 ; Zaragosi, Laure Emmanuelle 15 

1  Translational Genomics Research Institute, Phoenix, USA (GRID:grid.250942.8) (ISNI:0000 0004 0507 3225) 
2  Vanderbilt University Medical Center, Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916) 
3  University of Nottingham, Respiratory Medicine NIHR Biomedical Research Centre, Nottingham, UK (GRID:grid.4563.4) (ISNI:0000 0004 1936 8868) 
4  Yale School of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
5  Brigham and Women’s Hospital, Harvard Medical School, Division of Pulmonary and Critical Care Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
6  Vanderbilt University Medical Center, Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916); Department of Veterans Affairs Medical Center, Nashville, USA (GRID:grid.413806.8) 
7  Imperial College, National Heart and Lung Institute, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); Royal Brompton and Harefield NHS Foundation Trust, Department of Histopathology, London, UK (GRID:grid.421662.5) (ISNI:0000 0000 9216 5443) 
8  Royal Papworth Hospital NHS Foundation Trust, Pathology Research, Cambridge, UK (GRID:grid.412939.4) (ISNI:0000 0004 0383 5994) 
9  Royal Infirmary of Edinburgh, Department of Pathology, Edinburgh, UK (GRID:grid.418716.d) (ISNI:0000 0001 0709 1919); Edinburgh University Medical School, Division of Pathology, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
10  Baylor College of Medicine, Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X) 
11  Vanderbilt University Medical Center, Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916); Department of Veterans Affairs Medical Center, Nashville, USA (GRID:grid.413806.8); Vanderbilt University, Department of Cell and Developmental Biology, Nashville, USA (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217) 
12  Northwestern University, Division of Pulmonary and Critical Care Medicine, Chicago, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507) 
13  Icahn School of Medicine at Mount Sinai, Genetics and Genomic Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
14  Boston University School of Medicine, Department of Medicine, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558); Johnson & Johnson Innovation, Cambridge, USA (GRID:grid.189504.1) 
15  Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France (GRID:grid.429194.3) (ISNI:0000 0004 0638 0649) 
16  European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK (GRID:grid.225360.0) (ISNI:0000 0000 9709 7726) 
17  Stockholm University, SciLifeLab, Department of Molecular Biosciences, Stockholm, Sweden (GRID:grid.10548.38) (ISNI:0000 0004 1936 9377); Justus Liebig University, Cardiopulmonary Institute, Giessen, Germany (GRID:grid.8664.c) (ISNI:0000 0001 2165 8627) 
18  Arizona State University, Center for Biological Physics and Department of Physics, Tempe, USA (GRID:grid.215654.1) (ISNI:0000 0001 2151 2636) 
19  Wellcome Trust/CRUK Gurdon Institute, Cambridge, UK (GRID:grid.450000.1) (ISNI:0000 0004 0606 5024); University of Cambridge, Department Physiology, Development and Neuroscience, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
20  Helmholtz Zentrum München, Institute of Computational Biology, Oberschleißheim, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); Technical University Munich, Departments of Mathematics and Life Sciences, Munich, Germany (GRID:grid.6936.a) (ISNI:0000000123222966) 
21  Nice University-Affiliated Hospital, Pneumology Department, Nice, France (GRID:grid.460782.f) (ISNI:0000 0004 4910 6551) 
22  The Catholic University of Korea, Department of Biomedicine and Health Sciences, Seoul, Korea (GRID:grid.411947.e) (ISNI:0000 0004 0470 4224) 
23  Comprehensive Pneumology Center (CPC)/Institute of Lung Biology and Disease (ILBD), Helmholtz Zentrum München, Oberschleißheim, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); Member of the German Center for Lung Research (DZL), Munich, Germany (GRID:grid.452624.3) 
24  University Côte d’Azur, Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France (GRID:grid.460782.f) (ISNI:0000 0004 4910 6551); University Côte d’Azur, Hospital‐Related Biobank, Pasteur Hospital, Nice, France (GRID:grid.460782.f) (ISNI:0000 0004 4910 6551); FHU OncoAge, Pasteur Hospital, BP69, Nice cedex 01, France (GRID:grid.464719.9) (ISNI:0000 0004 0639 4696) 
25  Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, Australia (GRID:grid.415306.5) (ISNI:0000 0000 9983 6924); University of New South Wales, UNSW Cellular Genomics Futures Institute, Sydney, Australia (GRID:grid.1005.4) (ISNI:0000 0004 4902 0432) 
26  University of Bonn, Department for Genomics & Immunoregulation, LIMES-Institute, Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300); PRECISE Platform for Single Cell Genomics & Epigenomics, Germany Center for Neurodegenerative Diseases and University of Bonn, Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300) 
27  Cincinnati Children’s Hospital Medical Center, Cincinnati, USA (GRID:grid.239573.9) (ISNI:0000 0000 9025 8099) 
28  National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, USA (GRID:grid.48336.3a) (ISNI:0000 0004 1936 8075) 
29  KTH Royal Institute of Technology, SciLifeLab, Department of Gene Technology, Stockholm, Sweden (GRID:grid.5037.1) (ISNI:0000000121581746) 
30  Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); Boston Children’s Hospital, Division of Gastroenterology, Hepatology, and Nutrition, Boston, USA (GRID:grid.2515.3) (ISNI:0000 0004 0378 8438); Harvard Stem Cell Institute, Cambridge, USA (GRID:grid.511171.2); Harvard Medical School, Program in Immunology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
31  Harvard Stem Cell Institute, Cambridge, USA (GRID:grid.511171.2) 
32  Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cellular Genetics Programme, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382) 
33  Stanford University, Department of Biochemistry and Wall Center for Pulmonary Vascular Disease, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
34  University of Cambridge and NIHR Cambridge Biomedical Research Centre, Department of Surgery, Cambridge, UK (GRID:grid.454369.9) 
35  UCSD, Department of Bioengineering, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
36  University of Pittsburgh Medical Center, Division of Rheumatology, Department of Medicine, Pittsburgh, USA (GRID:grid.412689.0) (ISNI:0000 0001 0650 7433) 
37  Université Côte d’Azur, CHU de Nice, FHU OncoAge, Department of Pulmonary Medicine and Allergology, Nice, France (GRID:grid.410528.a) (ISNI:0000 0001 2322 4179); CNRS UMR 7275—Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, France (GRID:grid.4444.0) (ISNI:0000 0001 2112 9282) 
38  Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); Newcastle University, Biosciences Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK (GRID:grid.1006.7) (ISNI:0000 0001 0462 7212); Newcastle Hospitals NHS Foundation Trust, Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK (GRID:grid.420004.2) (ISNI:0000 0004 0444 2244) 
39  University of Groningen, GRIAC Research Institute, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands (GRID:grid.4830.f) (ISNI:0000 0004 0407 1981) 
40  University College London, UCL Respiratory, Division of Medicine, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
41  University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, the Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598); University of Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands (GRID:grid.4830.f) (ISNI:0000 0004 0407 1981) 
42  Cartana AB, Stockholm, Sweden (GRID:grid.4830.f) 
43  Team 4, IRCAN, FHU OncoAge, University Côte d’Azur, CNRS, INSERM, Nice CEDEX 02, France (GRID:grid.460782.f) (ISNI:0000 0004 4910 6551); University Côte d’Azur, Department of Pneumology and Oncology, CHU Nice, FHU OncoAge, Nice, France (GRID:grid.460782.f) (ISNI:0000 0004 4910 6551) 
44  Comma Soft AG, Bonn, Germany (GRID:grid.460782.f) 
45  University of Pittsburgh, Department of Medicine, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
46  Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) 
47  Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, Chicago, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507) 
48  Memorial Sloan Kettering Cancer Center, Computational and Systems Biology Program, Sloan Kettering Institute, New York, USA (GRID:grid.51462.34) (ISNI:0000 0001 2171 9952) 
49  Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary (GRID:grid.418331.c) (ISNI:0000 0001 2195 9606); University of Helsinki, Tukholmankatu, Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
50  Duke University School of Medicine, Department of Cell Biology, Regeneration Next Initiative, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
51  Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34); Howard Hughes Medical Institute, MIT, Department of Biology, Cambridge, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786); Genentech, South San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718) 
52  University of Pittsburgh, Division of Pulmonary, Allergy and Critical Care Medicine, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
53  National Jewish Health, Department of Pediatrics; Center for Genes, Environment, and Health, Denver, USA (GRID:grid.240341.0) (ISNI:0000 0004 0396 0728) 
54  Ragon Institute of MGH, MIT, and Harvard, Cambridge, USA (GRID:grid.461656.6) (ISNI:0000 0004 0489 3491); Koch Institute for Integrative Cancer Research, Institute for Medical Engineering and Science (IMES), Cambridge, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786); Massachusetts Institute of Technology, Department of Chemistry, Cambridge, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786) 
55  University of Michigan Medical School, Department of Internal Medicine, Gastroenterology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); University of Michigan Medical School, Department of Cell and Developmental Biology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); University of Michigan College of Engineering, Department of Biomedical Engineering, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
56  Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cellular Genetics Programme, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); University of Cambridge, JJ Thompson Ave, Department of Physics/Cavendish Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
57  Chan Zuckerberg Biohub, San Franscisco, USA (GRID:grid.499295.a) 
58  University of California, Department of Pediatrics, Respiratory Medicine, San Diego, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
59  Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) 
60  Stanford University School of Medicine, Department of Medicine and Institute for Stem Cell Biology and Regenerative Medicine, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
61  University of California, San Diego, Department of Pediatrics, San Diego, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); Laboratory of Genetics, University of Wisconsin–Madison, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-24467-0
ProQuest document ID
2551409771
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.