title: Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis.
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.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Yokoyama
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jesse W
authors.initials: JW
authors.lastname: Williams
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Baldridge
authors.affiliation: Department of Internal Medicine (Pulmonary and Critical Care Medicine), Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Internal Medicine (Pulmonary and Critical Care Medicine), Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: DesRochers
authors.affiliation: Department of Internal Medicine (Pulmonary and Critical Care Medicine), Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Traci
authors.initials: T
authors.lastname: Bricker
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Wilen
authors.affiliation: 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.
authors.forename: Juhi
authors.initials: J
authors.lastname: Bagaitkar
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Loginicheva
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Computer Technologies Department, ITMO University, St. Petersburg 197101, Russia.
authors.forename: Alexey
authors.initials: A
authors.lastname: Sergushichev
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Darren
authors.initials: D
authors.lastname: Kreamalmeyer
authors.affiliation: 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.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Keller
authors.affiliation: State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Amal
authors.initials: A
authors.lastname: Kambal
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: Immunity, Inflammation, and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, NC 27703, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martinez
authors.affiliation: 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.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Dinauer
authors.affiliation: Department of Internal Medicine (Pulmonary and Critical Care Medicine), Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Erika C
authors.initials: EC
authors.lastname: Crouch
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Wandy
authors.initials: W
authors.lastname: Beatty
authors.affiliation: Department of Internal Medicine (Pulmonary and Critical Care Medicine), Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Adrianus C M
authors.initials: AC
authors.lastname: Boon
authors.affiliation: State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Gwendalyn J
authors.initials: GJ
authors.lastname: Randolph
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Artyomov
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: virgin@wustl.edu.
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
mesh_terms: D000818:Animals; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D006706:Homeostasis; D006801:Humans; D007113:Immunity, Innate; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology*; D007251:Influenza, Human / Q000235:genetics / Q000276:immunology* / Q000821:virology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000276:immunology; D011014:Pneumonia / Q000235:genetics / Q000276:immunology* / Q000821:virology; D011506:Proteins / Q000235:genetics / Q000276:immunology*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000276:immunology
chemical_list: C561107:Atg14 protein, mouse; C502661:Atg7 protein, mouse; D000071183:Autophagy-Related Proteins; C581266:Epg5 protein, mouse; D008869:Microtubule-Associated Proteins; D011506:Proteins; D033921:Vesicular Transport Proteins; D000071193:Autophagy-Related Protein 7