title: Acute Lung Injury Results from Innate Sensing of Viruses by an ER Stress Pathway.
abstract: Incursions of new pathogenic viruses into humans from animal reservoirs are occurring with alarming frequency. The molecular underpinnings of immune recognition, host responses, and pathogenesis in this setting are poorly understood. We studied pandemic influenza viruses to determine the mechanism by which increasing glycosylation during evolution of surface proteins facilitates diminished pathogenicity in adapted viruses. ER stress during infection with poorly glycosylated pandemic strains activated the unfolded protein response, leading to inflammation, acute lung injury, and mortality. Seasonal strains or viruses engineered to mimic adapted viruses displaying excess glycans on the hemagglutinin did not cause ER stress, allowing preservation of the lungs and survival. We propose that ER stress resulting from recognition of non-adapted viruses is utilized to discriminate "non-self" at the level of protein processing and to activate immune responses, with unintended consequences on pathogenesis. Understanding this mechanism should improve strategies for treating acute lung injury from zoonotic viral infections.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Eike R
authors.initials: ER
authors.lastname: Hrincius
authors.affiliation: Institute of Molecular Virology (IMV), University of Muenster, Muenster 48149, Germany.
authors.forename: Swantje
authors.initials: S
authors.lastname: Liedmann
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Department of Veterinary Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: Gansebom
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN 38103, USA.
authors.forename: Amali E
authors.initials: AE
authors.lastname: Samarasinghe
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN 38103, USA.
authors.forename: Dahui
authors.initials: D
authors.lastname: You
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN 38103, USA.
authors.forename: Stephania A
authors.initials: SA
authors.lastname: Cormier
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN 38103, USA. Electronic address: jmccullers@uthsc.edu.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: McCullers
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D000818:Animals; D004285:Dogs; D059865:Endoplasmic Reticulum Stress / Q000276:immunology*; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology / Q000378:metabolism / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015398:Signal Transduction