A distinct monocyte transcriptional state links systemic immune dysregulation to pulmonary impairment in long COVID.

Summary

This multi-cohort single-cell multiome study identifies a pathogenic monocyte transcriptional state (LC-Mo) characterized by TGFβ/WNT-β-catenin signaling, persistent chemokine elevation, and AP-1/NF-κB1-driven profibrotic programs. LC-Mo abundance correlates with fatigue and severe respiratory symptoms, with BAL macrophages showing profibrotic profiles and impaired interferon responses.

Key Findings

• Identified LC-Mo monocyte state enriched after mild–moderate acute infection with persistent plasma CCL2, CXCL11, and TNF elevations.
• LC-Mo exhibits TGFβ and WNT-β-catenin signaling and AP-1/NF-κB1-driven profibrotic epigenetic programs.
• LC-Mo correlates with fatigue and severe respiratory symptoms; BAL macrophages show profibrotic profiles, and high LC-Mo associates with impaired interferon responses.

Clinical Implications

Potential to stratify long COVID patients using LC-Mo protein markers and to test pathway-directed interventions (e.g., TGFβ/WNT modulation). Supports integrating immune phenotyping into long COVID clinics.

Limitations

• Observational design limits causal inference
• Cohort heterogeneity and lack of interventional validation

Future Directions

Prospective validation of LC-Mo as a stratification biomarker; interventional studies targeting TGFβ/WNT/AP-1/NF-κB pathways; integration with pulmonary imaging and physiology.