Alveolar macrophages critically control infection by seasonal human coronavirus OC43 to avoid severe pneumonia.

Summary

In a mouse model of seasonal coronavirus OC43, loss of alveolar macrophages precipitated severe COVID-19-like pneumonia with neutrophil influx, NET formation, and cytokine amplification. Alveolar macrophages directly phagocytosed virus to limit spread; in their absence, TLR-driven chemokines fueled pathology, indicating AMs are central protectors against coronavirus lower respiratory disease.

Key Findings

• Alveolar macrophage deficiency converted otherwise mild HCoV-OC43 infection into severe COVID-19-like pneumonia in mice.
• AMs limited infection by phagocytosing HCoV-OC43; in their absence, TLR-dependent chemokines drove neutrophil infiltration and NET release.
• Innate sensing pathways and adaptive immune cells were not essential for protection against HCoV-OC43, highlighting AMs as central defenders.

Clinical Implications

Therapies preserving alveolar macrophage function (e.g., avoiding unnecessary macrophage-toxic regimens), targeted modulation of TLR signaling or NETs, and macrophage-supportive interventions could reduce coronavirus pneumonia severity.

Limitations

• Mouse OC43 model may not fully recapitulate human SARS-CoV-2 pathogenesis.
• Specific macrophage depletion approaches can have off-target effects; human validation is needed.

Future Directions

Validate AM-centric protection in human tissues or cohorts; test interventions enhancing AM function or modulating TLR/NET pathways in translational models.