Fibrosis is a major cause of mortality, with global death rates increasing in recent years. Whether genetic-related, malignant, infectious, autoimmune, or idiopathic, fibrosis can affect any organ.
Lung fibrosis poses a particular clinical issue due to the lack of effective therapies and poor understanding of its aetiology. With respect to the pathogenesis of fibrosis, attention has focussed on fibroblast activation, given its central role in the synthesis of collagen and other extracellular matrix proteins.
In this study, the authors used snRNA-sequencing in fixed tissue sections from patients suffering from Coronavirus Disease 2019 (COVID-19), and identified a ‘COVID‑19 signature’ in the lung ecosystem, consisting mainly of five molecular and cellular events:
- Monocyte/macrophage-derived IL‑1β and epithelial-derived IL‑6 production
- Impaired alveolar type 1 (AT1) regeneration
- Destruction of alveolar epithelium
- Expansion of JUN+ CTHRC1+ pathological fibroblasts
- Presence of ectopic tuft-like cells
The authors suggest that these mechanisms are likely triggers to pulmonary fibrosis and contribute to COVID‑19 fatality. They identified a reduction in alveolar type II (AT2) and type I (AT1) cells and an increase in monocytes/macrophages, fibroblasts, and neuronal cells.
Their data suggested an impaired T‑cell response in COVID‑19, although no significant increase in T‑cell count was found.
Further analysis revealed that monocyte-derived macrophages (MDMs), transitioning MDMs and resident macrophages were more frequent, highly, and aberrantly activated in COVID‑19.
The numbers of Tuft-like cells (ChAT+ or POU2F3+) were increased 3-fold in the upper airways, and they were ectopically present in the lung parenchyma of COVID‑19 patients, but not in control lungs.
αSMA immunohistochemistry revealed that fibroblasts were significantly increased in COVID‑19 lungs. Likewise, Sirius red staining and degree of fibrosis correlated with disease duration, indicating ensuing lung fibrosis over time in COVID‑19.
Different fibroblasts subtypes were identified: alveolar, adventitial, pathological, and intermediate pathological, and expansion of JUN++ CTHRC1+ pathological fibroblasts (pFB) was observed.
These pFB are critical drivers of lung fibrosis in murine models and in patients with idiopathic pulmonary fibrosis (IPF). Their increased frequency suggests pFB has a role in promoting rapidly evolving fibrosis in COVID‑19.
The authors also explored ligand-receptor interactions using CellPhoneDB across all major cell types and identified TGF‑β/STAT‑3/Jun signalling implicated in lung fibrosis.
The results of this study substantially extend previous publications by providing new insights into lung fibrosis and COVID‑19 pathophysiology. Significantly, the atlas provides a cellular landscape that will be a useful resource for therapeutic development.
Melms, J.C., Biermann, J., Huang, H. et al. A molecular single-cell lung atlas of lethal COVID-19. Nature (2021)