Daily Respiratory Research Analysis
Three mechanistic studies advance respiratory science: a spatially resolved multi-omic atlas maps early pro-inflammatory and late pro-fibrotic programs in COVID-19 alveolar damage (implicating PAI-1 and SPP1 signaling), human airway models identify basal cells as key SARS-CoV-2 targets with efficacy of local camostat, and compound screening reveals Wnt pathway activators that promote airway basal cell regeneration in vitro and in vivo.
Summary
Three mechanistic studies advance respiratory science: a spatially resolved multi-omic atlas maps early pro-inflammatory and late pro-fibrotic programs in COVID-19 alveolar damage (implicating PAI-1 and SPP1 signaling), human airway models identify basal cells as key SARS-CoV-2 targets with efficacy of local camostat, and compound screening reveals Wnt pathway activators that promote airway basal cell regeneration in vitro and in vivo.
Research Themes
- Spatially resolved pathophysiology of COVID-19 diffuse alveolar damage
- Airway epithelial cell tropism and local antiviral strategies
- Regenerative therapeutics via Wnt signaling for airway repair
Selected Articles
1. Integrated histopathology, spatial and single cell transcriptomics resolve cellular drivers of early and late alveolar damage in COVID-19.
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.
Impact: 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.
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.
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.
Methodological Strengths
- Integration of single-cell and spatial transcriptomics with histopathological staging.
- Cell–cell interaction analysis to infer signaling axes driving pathology.
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.
2. SARS-CoV-2 Infection of Human Lung Air-Liquid Interface Cultures Reveals Basal Cells as Relevant Targets.
Using primary human nasal/bronchial air–liquid interface cultures, SARS-CoV-2 (WT and Alpha) robustly infects basal cells, which substantially shape epithelial immune responses. Local camostat mesylate reduces viral load and immune activation in both basal and apical compartments.
Impact: Repositions basal cells as critical targets in early SARS-CoV-2 infection and provides preclinical evidence for intranasal serine protease inhibition as a practical early intervention.
Clinical Implications: Supports evaluating topical camostat for early upper-airway SARS-CoV-2 infection and guides epithelial cell-type–specific strategies for prophylaxis and treatment.
Key Findings
- Basal cells are strongly infected by SARS-CoV-2 (WT and Alpha) alongside ciliated and secretory cells.
- Basal cells significantly contribute to epithelial immune responses in a donor-specific manner.
- Topical camostat mesylate reduces viral load and immune activation in both basal and apical compartments.
Methodological Strengths
- Use of primary human nasal and bronchial ALI cultures with single-cell RNA-seq and spectral microscopy.
- Assessment across viral lineages (WT and Alpha) and cell compartments (basal and apical).
Limitations
- In vitro epithelial models may not fully recapitulate in vivo immune and tissue dynamics.
- Therapeutic findings with camostat are preclinical; clinical efficacy remains to be established.
Future Directions: Clinical trials of intranasal camostat; define basal cell-specific antiviral pathways and interactions with ciliated/secretory cells in vivo.
3. Compound screening in human airway basal cells identifies Wnt pathway activators as potential pro-regenerative therapies.
Phenotypic screening of 1,429 compounds in primary human airway basal cells identified 17 pro-proliferative hits, including Wnt pathway activators and abacavir. 1-azakenpaullone activated Wnt targets and expanded basal cells in mice, supporting Wnt modulation as a regenerative strategy.
Impact: Opens a translational path for pharmacologic enhancement of airway epithelial regeneration by targeting Wnt signaling in basal stem cells.
Clinical Implications: Provides candidate small molecules for airway repair after injury/infection; informs strategies for diseases with epithelial damage (e.g., COPD, post-viral injury) pending safety and efficacy studies.
Key Findings
- Screen of 1,429 compounds identified 17 validated pro-proliferative hits in human airway basal cells.
- Multiple Wnt pathway activators and abacavir increased basal cell proliferation in colony and 3D organoid assays.
- 1-azakenpaullone activated Wnt target genes and expanded basal cells in mice.
Methodological Strengths
- High-throughput phenotypic screen with validation across independent donor cells.
- Multi-system validation including colony, 3D organoid assays, and in vivo mouse data.
Limitations
- Proliferation does not guarantee functional mucociliary differentiation or barrier restoration.
- Wnt activation carries oncogenic risk; safety, dosing, and durability require careful testing.
Future Directions: Profile differentiation outcomes and mucociliary function after Wnt modulation; optimize dosing and delivery; assess safety in chronic injury models.