Pleural Mesothelial Cells Modulate the Inflammatory/Profibrotic Response During SARS-CoV-2 Infection

Area of Science:

• Pulmonology
• Virology
• Cell Biology

Background:

• Lung fibrosis is a significant complication of COVID-19, but its pathogenesis remains unclear.
• The involvement of the pleura, the membrane lining the lungs, in COVID-19-related fibrosis has not been established.
• Mesothelial cells (MCs) are key components of the pleura.

Purpose of the Study:

• To investigate the role of pleural mesothelial cells (MCs) in COVID-19-associated lung fibrosis.
• To determine if SARS-CoV-2 infects and affects pleural MCs.
• To analyze the inflammatory and fibrotic responses mediated by pleural MCs during SARS-CoV-2 infection.

Main Methods:

• Analysis of pleural autoptic samples from COVID-19 patients using immunohistochemistry for mesothelial cell markers (cytokeratins, WT1).
• In vitro studies using a human pleural MC line (MeT5A) to assess SARS-CoV-2 infection, replication, and receptor expression (ACE2, TMPRSS2, ADAM17, NRP1) via RT-PCR and Western blot.
• Measurement of inflammatory cytokines and metalloproteases in supernatants of infected MeT5A cells using Luminex and ELLA assays.

Main Results:

• COVID-19 pleura samples showed disrupted mesothelial layers and sub-mesothelial fibrosis with fibroblast-like MCs, but no direct SARS-CoV-2 infection in vivo.
• Pleural MCs in COVID-19 patients expressed ACE2, a key SARS-CoV-2 receptor.
• In vitro, MeT5A cells supported SARS-CoV-2 replication and expressed viral entry receptors, releasing interferons, inflammatory cytokines, and metalloproteases upon infection.

Conclusions:

• Pleural mesothelial cells (MCs) play a potential role in promoting fibrotic reactions in the pleura during SARS-CoV-2 infection.
• MCs can act as regulators of the immune response by producing inflammatory mediators.
• These findings suggest the pleura is involved in COVID-19 pathogenesis, contributing to fibrosis and immune dysregulation.