title: Deficiency of melanoma differentiation-associated protein 5 results in exacerbated chronic postviral lung inflammation.
abstract: BACKGROUND
  Respiratory viral infections can result in the establishment of chronic lung diseases. Understanding the early innate immune mechanisms that participate in the development of chronic postviral lung disease may reveal new targets for therapeutic intervention. The intracellular viral sensor protein melanoma differentiation-associated protein 5 (MDA5) sustains the acute immune response to Sendai virus, a mouse pathogen that causes chronic lung inflammation, but its role in the development of postviral chronic lung disease is unknown.
  
  
  OBJECTIVE
  To establish the role of MDA5 in the development of chronic lung disease.
  
  
  METHODS
  MDA5-deficient or control mice were infected with Sendai virus. The acute inflammatory response was evaluated by profiling chemokine and cytokine expression and by characterizing the composition of the cellular infiltrate. The impact of MDA5 on chronic lung pathology and function was evaluated through histological studies, degree of oxygen saturation, and responsiveness to carbachol.
  
  
  RESULTS
  MDA5 deficiency resulted in normal virus replication and in a distinct profile of chemokines and cytokines that associated with acute lung neutropenia and enhanced accumulation of alternatively activated macrophages. Diminished expression of neutrophil-recruiting chemokines was also observed in cells infected with influenza virus, suggesting a key role of MDA5 in driving the early accumulation of neutrophils at the infection site. The biased acute inflammatory response of MDA5-deficient mice led to an enhanced chronic lung inflammation, epithelial cell hyperplasia, airway hyperreactivity, and diminished blood oxygen saturation.
  
  
  CONCLUSIONS
  MDA5 modulates the development of chronic lung inflammation by regulating the early inflammatory response in the lung.
authors.affiliation: 1 Department of Pathobiology, School of Veterinary Medicine, and.
authors.forename: Won-Keun
authors.initials: WK
authors.lastname: Kim
authors.forename: Deepika
authors.initials: D
authors.lastname: Jain
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Sánchez
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Koziol-White
authors.forename: Krystal
authors.initials: K
authors.lastname: Matthews
authors.forename: Moyar Q
authors.initials: MQ
authors.lastname: Ge
authors.forename: Angela
authors.initials: A
authors.lastname: Haczku
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Frieman
authors.forename: Carolina B
authors.initials: CB
authors.lastname: López
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D018925:Chemokines / Q000378:metabolism; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000172:deficiency*; D005434:Flow Cytometry; D007113:Immunity, Innate; D000072640:Interferon-Induced Helicase, IFIH1; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011024:Pneumonia, Viral / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D010253:Respirovirus Infections / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D029082:Sendai virus
chemical_list: D015415:Biomarkers; D018925:Chemokines; D016207:Cytokines; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1