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Increased SARS-CoV-2 Infection, Protease, and Inflammatory Responses in Chronic Obstructive Pulmonary Disease Primary Bronchial Epithelial Cells Defined with Single-Cell RNA Sequencing.
Am J Respir Crit Care Med. 2022 09 15; 206(6):712-729.AJ

Abstract

Rationale: Patients with chronic obstructive pulmonary disease (COPD) develop more severe coronavirus disease (COVID-19); however, it is unclear whether they are more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and what mechanisms are responsible for severe disease. Objectives: To determine whether SARS-CoV-2 inoculated primary bronchial epithelial cells (pBECs) from patients with COPD support greater infection and elucidate the effects and mechanisms involved. Methods: We performed single-cell RNA sequencing analysis on differentiated pBECs from healthy subjects and patients with COPD 7 days after SARS-CoV-2 inoculation. We correlated changes with viral titers, proinflammatory responses, and IFN production. Measurements and Main Results: Single-cell RNA sequencing revealed that COPD pBECs had 24-fold greater infection than healthy cells, which was supported by plaque assays. Club/goblet and basal cells were the predominant populations infected and expressed mRNAs involved in viral replication. Proteases involved in SARS-CoV-2 entry/infection (TMPRSS2 and CTSB) were increased, and protease inhibitors (serpins) were downregulated more so in COPD. Inflammatory cytokines linked to COPD exacerbations and severe COVID-19 were increased, whereas IFN responses were blunted. Coexpression analysis revealed a prominent population of club/goblet cells with high type 1/2 IFN responses that were important drivers of immune responses to infection in both healthy and COPD pBECs. Therapeutic inhibition of proteases and inflammatory imbalances reduced viral titers and cytokine responses, particularly in COPD pBECs. Conclusions: COPD pBECs are more susceptible to SARS-CoV-2 infection because of increases in coreceptor expression and protease imbalances and have greater inflammatory responses. A prominent cluster of IFN-responsive club/goblet cells emerges during infection, which may be important drivers of immunity. Therapeutic interventions suppress SARS-CoV-2 replication and consequent inflammation.

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Authors+Show Affiliations

Johansen MD
Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute, University of Technology Sydney, Sydney, New South Wales, Australia.
Mahbub RM
Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute, University of Technology Sydney, Sydney, New South Wales, Australia.
Idrees S
Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute, University of Technology Sydney, Sydney, New South Wales, Australia.
Nguyen DH
Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute, University of Technology Sydney, Sydney, New South Wales, Australia.
Miemczyk S
Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute, University of Technology Sydney, Sydney, New South Wales, Australia.
Pathinayake P
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
Nichol K
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
Hansbro NG
Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute, University of Technology Sydney, Sydney, New South Wales, Australia.
Gearing LJ
Department of Molecular and Translational Sciences, School of Clinical Sciences at Monash Health, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
Hertzog PJ
Department of Molecular and Translational Sciences, School of Clinical Sciences at Monash Health, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
Gallego-Ortega D
Faculty of Engineering and Information Technology, School of Biomedical Engineering, Centre for Single Cell Technology, University of Technology Sydney, Ultimo, New South Wales, Australia. Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Kensington, New South Wales, Australia; and.
Britton WJ
Centenary Institute, University of Sydney and Department of Clinical Immunology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
Saunders BM
Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute, University of Technology Sydney, Sydney, New South Wales, Australia.
Wark PA
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
Faiz A
Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute, University of Technology Sydney, Sydney, New South Wales, Australia.
Hansbro PM
Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute, University of Technology Sydney, Sydney, New South Wales, Australia. Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.

MeSH

COVID-19CytokinesEpithelial CellsHumansPeptide HydrolasesPulmonary Disease, Chronic ObstructiveSARS-CoV-2Sequence Analysis, RNASerpins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

35549656

Citation

Johansen, Matt D., et al. "Increased SARS-CoV-2 Infection, Protease, and Inflammatory Responses in Chronic Obstructive Pulmonary Disease Primary Bronchial Epithelial Cells Defined With Single-Cell RNA Sequencing." American Journal of Respiratory and Critical Care Medicine, vol. 206, no. 6, 2022, pp. 712-729.
Johansen MD, Mahbub RM, Idrees S, et al. Increased SARS-CoV-2 Infection, Protease, and Inflammatory Responses in Chronic Obstructive Pulmonary Disease Primary Bronchial Epithelial Cells Defined with Single-Cell RNA Sequencing. Am J Respir Crit Care Med. 2022;206(6):712-729.
Johansen, M. D., Mahbub, R. M., Idrees, S., Nguyen, D. H., Miemczyk, S., Pathinayake, P., Nichol, K., Hansbro, N. G., Gearing, L. J., Hertzog, P. J., Gallego-Ortega, D., Britton, W. J., Saunders, B. M., Wark, P. A., Faiz, A., & Hansbro, P. M. (2022). Increased SARS-CoV-2 Infection, Protease, and Inflammatory Responses in Chronic Obstructive Pulmonary Disease Primary Bronchial Epithelial Cells Defined with Single-Cell RNA Sequencing. American Journal of Respiratory and Critical Care Medicine, 206(6), 712-729. https://doi.org/10.1164/rccm.202108-1901OC
Johansen MD, et al. Increased SARS-CoV-2 Infection, Protease, and Inflammatory Responses in Chronic Obstructive Pulmonary Disease Primary Bronchial Epithelial Cells Defined With Single-Cell RNA Sequencing. Am J Respir Crit Care Med. 2022 09 15;206(6):712-729. PubMed PMID: 35549656.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased SARS-CoV-2 Infection, Protease, and Inflammatory Responses in Chronic Obstructive Pulmonary Disease Primary Bronchial Epithelial Cells Defined with Single-Cell RNA Sequencing. AU - Johansen,Matt D, AU - Mahbub,Rashad M, AU - Idrees,Sobia, AU - Nguyen,Duc H, AU - Miemczyk,Stefan, AU - Pathinayake,Prabuddha, AU - Nichol,Kristy, AU - Hansbro,Nicole G, AU - Gearing,Linden J, AU - Hertzog,Paul J, AU - Gallego-Ortega,David, AU - Britton,Warwick J, AU - Saunders,Bernadette M, AU - Wark,Peter A, AU - Faiz,Alen, AU - Hansbro,Philip M, PY - 2022/5/14/pubmed PY - 2022/9/21/medline PY - 2022/5/13/entrez KW - COPD KW - COVID-19 KW - interferon KW - protease KW - single-cell RNA sequencing SP - 712 EP - 729 JF - American journal of respiratory and critical care medicine JO - Am J Respir Crit Care Med VL - 206 IS - 6 N2 - Rationale: Patients with chronic obstructive pulmonary disease (COPD) develop more severe coronavirus disease (COVID-19); however, it is unclear whether they are more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and what mechanisms are responsible for severe disease. Objectives: To determine whether SARS-CoV-2 inoculated primary bronchial epithelial cells (pBECs) from patients with COPD support greater infection and elucidate the effects and mechanisms involved. Methods: We performed single-cell RNA sequencing analysis on differentiated pBECs from healthy subjects and patients with COPD 7 days after SARS-CoV-2 inoculation. We correlated changes with viral titers, proinflammatory responses, and IFN production. Measurements and Main Results: Single-cell RNA sequencing revealed that COPD pBECs had 24-fold greater infection than healthy cells, which was supported by plaque assays. Club/goblet and basal cells were the predominant populations infected and expressed mRNAs involved in viral replication. Proteases involved in SARS-CoV-2 entry/infection (TMPRSS2 and CTSB) were increased, and protease inhibitors (serpins) were downregulated more so in COPD. Inflammatory cytokines linked to COPD exacerbations and severe COVID-19 were increased, whereas IFN responses were blunted. Coexpression analysis revealed a prominent population of club/goblet cells with high type 1/2 IFN responses that were important drivers of immune responses to infection in both healthy and COPD pBECs. Therapeutic inhibition of proteases and inflammatory imbalances reduced viral titers and cytokine responses, particularly in COPD pBECs. Conclusions: COPD pBECs are more susceptible to SARS-CoV-2 infection because of increases in coreceptor expression and protease imbalances and have greater inflammatory responses. A prominent cluster of IFN-responsive club/goblet cells emerges during infection, which may be important drivers of immunity. Therapeutic interventions suppress SARS-CoV-2 replication and consequent inflammation. SN - 1535-4970 UR - https://www.unboundmedicine.com/medline/citation/35549656/Increased_SARS_CoV_2_Infection_Protease_and_Inflammatory_Responses_in_Chronic_Obstructive_Pulmonary_Disease_Primary_Bronchial_Epithelial_Cells_Defined_with_Single_Cell_RNA_Sequencing_ DB - PRIME DP - Unbound Medicine ER -