title: Autophagy Genes Enhance Murine Gammaherpesvirus 68 Reactivation from Latency by Preventing Virus-Induced Systemic Inflammation.
abstract: Host genes that regulate systemic inflammation upon chronic viral infection are incompletely understood. Murine gammaherpesvirus 68 (MHV68) infection is characterized by latency in macrophages, and reactivation is inhibited by interferon-γ (IFN-γ). Using a lysozyme-M-cre (LysMcre) expression system, we show that deletion of autophagy-related (Atg) genes Fip200, beclin 1, Atg14, Atg16l1, Atg7, Atg3, and Atg5, in the myeloid compartment, inhibited MHV68 reactivation in macrophages. Atg5 deficiency did not alter reactivation from B cells, and effects on reactivation from macrophages were not explained by alterations in productive viral replication or the establishment of latency. Rather, chronic MHV68 infection triggered increased systemic inflammation, increased T cell production of IFN-γ, and an IFN-γ-induced transcriptional signature in macrophages from Atg gene-deficient mice. The Atg5-related reactivation defect was partially reversed by neutralization of IFN-γ. Thus Atg genes in myeloid cells dampen virus-induced systemic inflammation, creating an environment that fosters efficient MHV68 reactivation from latency.
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Sunmin
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Buck
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Chandni
authors.initials: C
authors.lastname: Desai
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Loginicheva
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: Division of Infectious Diseases, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Freeman
authors.affiliation: Division of Molecular Genetics, Institute for Enzyme Research, Tokushima University, 3-8-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Saitoh
authors.affiliation: Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: You-Wen
authors.initials: YW
authors.lastname: He
authors.affiliation: Trudeau Institute, Saranac Lake, NY 12983, USA.
authors.forename: Marcia A
authors.initials: MA
authors.lastname: Blackman
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Handley
authors.affiliation: Center for Autophagy Research, Department of Internal Medicine and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
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: Department of Immunology and Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Reese
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Artyomov
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA. Electronic address: virgin@wustl.edu.
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
mesh_terms: D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology* / Q000821:virology; D054884:Host-Pathogen Interactions; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology; D018144:Rhadinovirus / Q000235:genetics / Q000502:physiology*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000276:immunology; D014775:Virus Activation; D017735:Virus Latency
chemical_list: C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D008869:Microtubule-Associated Proteins; D007371:Interferon-gamma; D044763:Ubiquitin-Conjugating Enzymes; D000071193:Autophagy-Related Protein 7; C568853:Atg3 protein, mouse