title: Epigenetic and Transcriptomic Regulation of Lung Repair during Recovery from Influenza Infection.
abstract: Seasonal and pandemic influenza is a cause of morbidity and mortality worldwide. Most people infected with influenza virus display mild-to-moderate disease phenotypes and recover within a few weeks. Influenza is known to cause persistent alveolitis in animal models; however, little is known about the molecular pathways involved in this phenotype. We challenged C57BL/6 mice with influenza A/PR/8/34 and examined lung pathologic processes and inflammation, as well as transcriptomic and epigenetic changes at 21 to 60 days after infection. Influenza induced persistent parenchymal lung inflammation, alveolar epithelial metaplasia, and epithelial endoplasmic reticulum stress that were evident after the clearance of virus and resolution of morbidity. Influenza infection induced robust changes in the lung transcriptome, including a significant impact on inflammatory and extracellular matrix protein expression. Despite the robust changes in lung gene expression, preceding influenza (21 days) did not exacerbate secondary Staphylococcus aureus infection. Finally, we examined the impact of influenza on miRNA expression in the lung and found an increase in miR-155. miR-155 knockout mice recovered from influenza infection faster than controls and had decreased lung inflammation and endoplasmic reticulum stress. These data illuminate the dynamic molecular changes in the lung in the weeks after influenza infection and characterize the repair process, identifying a novel role for miR-155.
authors.affiliation: Department of Pulmonary Critical Care and Environmental Medicine, Tulane University School of Medicine, New Orleans, Louisiana; Richard K. Mellon Foundation Institute, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Pociask
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Keven M
authors.initials: KM
authors.lastname: Robinson
authors.affiliation: Richard K. Mellon Foundation Institute, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Kong
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: McHugh
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Clay
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; PhD Program in Computational Biology, Carnegie Mellon University and University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Grace T
authors.initials: GT
authors.lastname: Huang
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Panayiotis V
authors.initials: PV
authors.lastname: Benos
authors.affiliation: Department of Pathology, University of Vermont, Burlington, Vermont.
authors.forename: Yvonne M W
authors.initials: YMW
authors.lastname: Janssen-Heininger
authors.affiliation: Richard K. Mellon Foundation Institute, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.affiliation: Department of Pathology, University of Vermont, Burlington, Vermont.
authors.forename: Vikas
authors.initials: V
authors.lastname: Anathy
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania. Electronic address: john.alcorn@chp.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: Alcorn
mesh_terms: D000818:Animals; D018450:Disease Progression; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D044127:Epigenesis, Genetic; D004848:Epithelium / Q000473:pathology; D020869:Gene Expression Profiling; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000821:virology*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology; D011014:Pneumonia / Q000209:etiology / Q000382:microbiology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D059467:Transcriptome / Q000235:genetics*; D014945:Wound Healing / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse