Homeostatic Control of Innate Immune Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis

Mutations in the autophagy gene EPG5 are linked to the multisystem human disease Vici syndrome, characterized by neurologic, muscular, and pulmonary abnormalities. We found that Epg5-/- mice exhibited elevated baseline innate immune cellular and cytokine-based lung inflammation and were resistant to lethal influenza virus infection. Lung transcriptomics, bone marrow transplantation experiments, and analysis cellular cytokine expression indicated that Epg5 plays a role in lung physiology, likely through its function in macrophages. Deletion of other autophagy genes including Atg14, FIP200, Atg5, and Atg7 in myeloid cells also led to elevated lung inflammation and influenza resistance. This suggests that Epg5 and other Atg genes function in macrophages to limit innate immune inflammation in the lung. Disruption of this normal homeostatic dampening of lung inflammation results in increased resistance to influenza.