Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19

Area of Science:

• Immunology
• Pulmonology
• Pathology

Background:

• Post-Acute Sequelae of COVID-19 (PASC) presents significant long-term health challenges, with poorly understood mechanisms.
• Growing evidence links PASC to aberrant immune responses and compromised organ recovery, particularly in the lungs.
• The exact drivers of persistent inflammation and impaired tissue repair in respiratory PASC require elucidation.

Approach:

• Developed a mouse model for post-viral lung sequelae, mirroring human respiratory PASC.
• Utilized spatial transcriptomics and imaging to analyze immune cell-epithelial progenitor interactions in PASC lung tissue.
• Investigated the roles of CD8+ T cells, macrophages, and specific cytokines (IFN-γ, TNF, IL-1β) in driving fibrosis.

Key Points:

• Dysregulated interactions between lung-resident CD8+ T cells and macrophages maintain abnormal epithelial progenitors in respiratory PASC.
• This immune-epithelial crosstalk impairs alveolar regeneration and promotes pulmonary fibrosis, distinct from acute COVID-19 or IPF.
• CD8+ T cell-derived IFN-γ and TNF activate macrophages to release IL-1β, leading to dysplastic epithelial cell accumulation and fibrosis.

Conclusions:

• Respiratory PASC is driven by a disrupted immune-epithelial progenitor niche.
• Therapeutic targeting of IFN-γ, TNF, or IL-1β post-infection can reverse lung fibrosis and restore function.
• These findings offer novel therapeutic strategies for managing PASC and other post-viral fibrotic lung diseases.