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Cell Host Microbe. 2016 Jan 13;19(1):102-13. doi: 10.1016/j.chom.2015.12.011.

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

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Department of Internal Medicine (Pulmonary and Critical Care Medicine), Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pediatrics (Hematology/Oncology), Washington University School of Medicine, St. Louis, MO 63110, USA.
4
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Computer Technologies Department, ITMO University, St. Petersburg 197101, Russia.
5
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Internal Medicine (Pulmonary and Critical Care Medicine), Washington University School of Medicine, St. Louis, MO 63110, USA.
6
State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
7
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
8
Immunity, Inflammation, and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, NC 27703, USA.
9
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
10
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: virgin@wustl.edu.

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.

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PMID:
26764600
PMCID:
PMC4714358
DOI:
10.1016/j.chom.2015.12.011
[Indexed for MEDLINE]
Free PMC Article

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