Abstract
Post-COVID-19 residual lung abnormalities (RLA) are associated with persistent respiratory symptoms and radiological changes, yet the underlying mechanisms remain unclear. We performed integrated multi-omic profiling of paired bronchoalveolar lavage and blood samples from patients with post-COVID-19 RLA and healthy controls, combining single-cell RNA sequencing, CITE-seq, single-cell T cell receptor sequencing, bronchoalveolar lavage fluid proteomics and functional fibroblast assays. In post-COVID-19 RLA lungs, we identified an increased abundance of profibrotic SPP1hi monocyte-derived alveolar macrophages, arising from an expanded circulating HLA-DRlowCD163+PDE4Dhi classical monocyte progenitor population, supporting a blood-lung myeloid axis. Cell-cell communication modelling positioned macrophages as central hubs of immune-stromal crosstalk, promoting monocyte recruitment with profibrotic priming, and fibroblast activation. Proteomic analysis of bronchoalveolar lavage fluid from post-COVID-19 RLA and idiopathic pulmonary fibrosis, compared with healthy controls, revealed shared and distinct signatures. These alveolar proteins in post-COVID-19 RLA were predominantly attributed to myeloid cells and predicted to engage fibroblast receptors. Bronchoalveolar lavage fluid induced fibroblast proliferation, differentiation and collagen deposition in vitro, with proliferation attenuated by the antifibrotic drug nintedanib. We also identified compartment-specific lymphoid dysregulation, including depletion of mucosal-associated invariant T (MAIT) cells in both the lung and blood, decreased natural killer (NK) cells with oligoclonal T cell expansion in the lung, and expansion of regulatory and cytotoxic T cells in the blood. These findings support a persistent monocyte-macrophage-fibroblast axis linking immune dysregulation to fibroproliferative remodelling after COVID-19 and highlights candidate therapeutic targets for post-viral lung fibrosis. We provide a publicly available atlas at x (TBA).
Authors and Affiliations
Puja Mehta¹˒²˒³˒⁴†, Connar M. A. Mawer³˒⁵, Gordon Beattie⁶˒⁷, David J. F. Smith⁸, Fadi Nikola⁵, Hugh Selway-Clarke³, Amy Y. Zhao⁵, Taylor Adams⁵, Annabel Kunzemann-Martinez³, Stefan C. Stanel⁹, Kaylee B. Worlock³, Masahiro Yoshida³, Rachel Walters³, Sian Goldsworthy¹⁰˒¹¹, Imran Uddin⁷˒¹¹, Josephine L. Barnes³, Gabrielle J. Rockett¹², Marko Z. Nikolić³, Paolo Piazza¹², Manuela Platé³, Iain Stewart⁸, Joanna C. Porter³, Arjun Nair³˒¹³, Joseph Jacob³˒¹⁴, Xiting Yan⁵˒¹⁵, Naftali Kaminski⁵*, Ahmed S. N. Alhendi³*, and Rachel C. Chambers³*
¹ Section of Rheumatology, Allergy, and Immunology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
² Department of Biomedical Informatics and Data Science (BIDS), Yale School of Medicine, New Haven, CT, USA
³ UCL Respiratory, Division of Medicine, University College London, London, UK
⁴ Department of Medicine, Imperial College London
⁵ Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
⁶ CRUK City of London Centre Single Cell and Spatial Genomics Facility, UCL Cancer Institute, University College London, London, UK
⁷ Bioinformatics Hub, UCL Cancer Institute, University College London, London, UK
⁸ National Heart and Lung Institute (NHLI), Imperial College London, London, UK
⁹ Department of Respiratory Medicine, University of Exeter, Exeter, UK
¹⁰ Great Ormond Street Institute of Child Health, Faculty of Population Health Sciences, University College London, London, UK
¹¹ Genomics Translational Technology Platform, UCL Cancer Institute, University College London, London, UK
¹² Nuffield Department of Medicine, Centre for Human Genetics, University of Oxford, Oxford, UK
¹³ Department of Radiology, University College London Hospitals NHS Foundation Trust, London, UK
¹⁴ Satsuma Lab, Hawkes Institute, University College London, London, UK
¹⁵ Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA
† Corresponding author: Puja Mehta
\* Naftali Kaminski, Ahmed S. N. Alhendi, and Rachel C. Chambers share the author designation indicated in the source.