Abstract
To elucidate the important cellular and molecular drivers of pulmonary long COVID, we generated a single-cell transcriptomic map of the airway mucosa using bronchial brushings from patients with long COVID who reported persistent pulmonary symptoms.
Adults with and without long COVID were recruited from the general community in Greater Vancouver, Canada. The cohort was divided into those with pulmonary long COVID (PLC), which was defined as persons with new or worsening respiratory symptoms following at least one year from their initial acute SARS-CoV-2 infection (N=9); and control subjects defined as SARS-CoV-2 infected persons whose acute respiratory symptoms had fully resolved or individuals who had no history of acute COVID-19 (N=9). These participants underwent bronchoscopy from which a single cell suspension was created from bronchial brush samples and then sequenced.
A total of 56 906 cells were recovered for the downstream analysis, with 34 840 cells belonging to the PLC group, which strikingly showed a unique cluster of neutrophils in the PLC group (p<0.05). Ingenuity Pathway Analysis revealed that the neutrophil degranulation pathway was enriched across epithelial cell clusters. Differential gene expression analysis between the PLC and control groups demonstrated upregulation of inflammatory chemokines and epithelial barrier dysfunction across epithelial cell clusters, as well as over-expression of mucin genes across secretory cell clusters.
In conclusion, a single-cell transcriptomic landscape of the small airways suggest that neutrophils may play a significant role in mediating the chronic small airway inflammation driving pulmonary symptoms of long COVID.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: EVA received support for this work from the Swedish Research Council, the Strategic Research Area in Epidemiology (SfoEpi) at Karolinska Institutet and the Sven and Ebba Hagberg Prize. EVA received an honorarium for grant review from the Milken Institute.
Conflict of interest: D. Sin reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, AstraZeneca, Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board with NHLBI.
Conflict of interest: F. Geraveli reports grants from MiTACS Accelerate.
Conflict of interest: H.Y. Park has nothing to disclose.
Conflict of interest: S. Milne reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Chiesi Australia, The Limbic Australia, Research Review Australia, support for attending meetings from Sanofi Australia, Chiesi Australia, AstraZeneca, and a leadership role with Thoracic Society of Australia and New Zealand (NSW/ACT).
Conflict of interest: X. Li has nothing to disclose.
Conflict of interest: C.X. Yang has nothing to disclose.
Conflict of interest: J. Tuong has nothing to disclose.
Conflict of interest: R. Eddy reports grants from Michael Smith Health Research BC, Canadian Respiratory Research Network and Natural Sciences and Engineering Research Council Canada, consultancy fees from VIDA Diagnostics Inc., payment or honoraria for lectures, presentations, manuscript writing or educational events from Thorasys Thoracic Medical Systems Inc., and support for attending meetings from Canadian Institutes of Health Research – Institute of Circulatory and Respiratory Health.
Conflict of interest: E. Guinto has nothing to disclose.
Conflict of interest: C. Cheung has nothing to disclose.
Conflict of interest: S-W. J. Yang has nothing to disclose.
Conflict of interest: S.M. Vahedi has nothing to disclose.
Conflict of interest: C. Gilchrist reports grants from Canadian institutes of Health Research.
Conflict of interest: D. Yehia has nothing to disclose.
Conflict of interest: H. Dang has nothing to disclose.
Conflict of interest: T. Stach has nothing to disclose.
Conflict of interest: C. Leung has nothing to disclose.
Conflict of interest: T. Shaipanich has nothing to disclose.
Conflict of interest: J. Leipsic reports consultancy fees from Heartflow, and stock (or stock options) with Heartflow.
Conflict of interest: G. Koelwyn has nothing to disclose.
Conflict of interest: J. Leung reports support for the present study from Canadian Institutes of Health Research, grants from Canadian Institutes of Health Research, BC Lung Foundation, payment or honoraria for lectures, presentations, manuscript writing or educational events from BC Lung Foundation, University of British Columbia, participation on a data safety monitoring board with Enhance Quality Safety, and Patient experience in Chronic Obstructive Pulmonary Disorder (EQuiP COPD), and leadership roles with Canadian Respiratory Research Network, CanCOLD Study.
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- Received November 2, 2023.
- Accepted September 4, 2024.
- Copyright ©The authors 2024. For reproduction rights and permissions contact permissions{at}ersnet.org
