Integrated histopathology, spatial and single cell transcriptomics resolve cellular drivers of early and late alveolar damage in COVID-19.
Summary
A multi-omic atlas across histological stages of diffuse alveolar damage in COVID-19 reveals early interferon/metallothionein programs and late pro-fibrotic collagen signatures, with endothelial SERPINE1/PAI-1 upregulation suggesting fibrinolytic shutdown. Macrophage-derived SPP1 signaling emerges as a key early regulator.
Key Findings
- Early diffuse alveolar damage shows interferon-alpha and metallothionein immune signatures.
- Late-stage lesions are enriched for fibrosis-related collagens (pro-fibrotic programs).
- Endothelial SERPINE1/PAI-1 is upregulated, predicting fibrinolytic shutdown.
- Macrophage-derived SPP1/osteopontin signaling acts as a key early regulator.
Clinical Implications
Suggests stage-specific therapeutic strategies: early modulation of macrophage SPP1 and interferon-metallothionein responses, and later anti-fibrotic/anti-PAI-1 approaches to prevent fibrinolytic shutdown and fibrosis.
Why It Matters
Defines spatially resolved cellular programs that drive inflammatory and fibrotic pathways in severe COVID-19 and nominates tractable targets (e.g., PAI-1, SPP1) for intervention.
Limitations
- Primarily observational and correlative; functional validation of predicted targets is needed.
- Findings derive from COVID-19 lungs and may not generalize to non-COVID diffuse alveolar damage.
Future Directions
Test PAI-1 inhibition and SPP1 pathway modulation in preclinical models; develop stage-tailored interventions guided by spatial biomarkers.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic, multi-omic observational analysis
- Study Design
- OTHER