Abstract
Mutations in the autophagy gene EPG5 are linked to the multisystem human disease Vici syndrome, which is characterized in part by pulmonary abnormalities, including recurrent infections. We found that Epg5-deficient 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 of cellular cytokine expression indicated that Epg5 plays a role in lung physiology through its function in macrophages. Deletion of other autophagy genes including Atg14, Fip200, Atg5, and Atg7 in myeloid cells also led to elevated basal 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, suggesting that normal homeostatic mechanisms that limit basal tissue inflammation support some infectious diseases.
Original language | English (US) |
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Pages (from-to) | 102-113 |
Number of pages | 12 |
Journal | Cell Host and Microbe |
Volume | 19 |
Issue number | 1 |
DOIs | |
State | Published - Jan 13 2016 |
Bibliographical note
Funding Information:We thank Xinyu Wang and Stoyan Ivanov for technical assistance. This work was supported by NIH awards U19AI109725 (H.W.V.), U19AI070489 (M.J.H.), RO1AI111605 (M.J.H.), RO1HL121791 (M.J.H.), and AI049653 (G.J.R.) and training grants T32AI007163 (C.C.Y.), T32DK7296 (J.W.W.), T32CA009547 (M.T.B.), and T32HL07317 (B.C.K.). This work was also supported by the WM Keck Fellowship from Washington University (M.T.B.), Washington University School of Medicine (A.C.M.B.), the Children''s Discovery Institute of Washington University and St. Louis Children''s Hospital (M.C.D., J.B.), the Howard Hughes Medical Institute (H.Z.), and grant 2013CB910100 from the National Basic Research Program of China (H.Z.).
Funding Information:
We thank Xinyu Wang and Stoyan Ivanov for technical assistance. This work was supported by NIH awards U19AI109725 (H.W.V.), U19AI070489 (M.J.H.), RO1AI111605 (M.J.H.), RO1HL121791 (M.J.H.), and AI049653 (G.J.R.) and training grants T32AI007163 (C.C.Y.), T32DK7296 (J.W.W.), T32CA009547 (M.T.B.), and T32HL07317 (B.C.K.). This work was also supported by the WM Keck Fellowship from Washington University (M.T.B.), Washington University School of Medicine (A.C.M.B.), the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (M.C.D., J.B.), the Howard Hughes Medical Institute (H.Z.), and grant 2013CB910100 from the National Basic Research Program of China (H.Z.).
Publisher Copyright:
© 2016 Elsevier Inc.