title: Proinflammatory effects of interferon gamma in mouse adenovirus 1 myocarditis.
abstract: Adenoviruses are frequent causes of pediatric myocarditis. Little is known about the pathogenesis of adenovirus myocarditis, and the species specificity of human adenoviruses has limited the development of animal models, which is a significant barrier to strategies for prevention or treatment. We have developed a mouse model of myocarditis following mouse adenovirus 1 (MAV-1) infection to study the pathogenic mechanisms of this important cause of pediatric myocarditis. Following intranasal infection of neonatal C57BL/6 mice, we detected viral replication and induction of interferon gamma (IFN-γ) in the hearts of infected mice. MAV-1 caused myocyte necrosis and induced substantial cellular inflammation that was composed predominantly of CD3(+) T lymphocytes. Depletion of IFN-γ during acute infection reduced cardiac inflammation in MAV-1-infected mice without affecting viral replication. We observed decreased contractility during acute infection of neonatal mice, and persistent viral infection in the heart was associated with cardiac remodeling and hypertrophy in adulthood. IFN-γ is a proinflammatory mediator during adenovirus-induced myocarditis, and persistent adenovirus infection may contribute to ongoing cardiac dysfunction.
  
  
  OBJECTIVE
  Studying the pathogenesis of myocarditis caused by different viruses is essential in order to characterize both virus-specific and generalized factors that contribute to disease. Very little is known about the pathogenesis of adenovirus myocarditis, which is a significant impediment to the development of treatment or prevention strategies. We used MAV-1 to establish a mouse model of human adenovirus myocarditis, providing the means to study host and pathogen factors contributing to adenovirus-induced cardiac disease during acute and persistent infection. The MAV-1 model will enable fundamental studies of viral myocarditis, including IFN-γ modulation as a therapeutic strategy.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Mary K
authors.initials: MK
authors.lastname: McCarthy
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Procario
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Nele
authors.initials: N
authors.lastname: Twisselmann
authors.affiliation: Unit for Laboratory Animal Research, University of Michigan, Ann Arbor, Michigan, USA Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: J Erby
authors.initials: JE
authors.lastname: Wilkinson
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Archambeau
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Michele
authors.affiliation: Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Sharlene M
authors.initials: SM
authors.lastname: Day
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA jbwein@umich.edu.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000032:analysis; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism*; D008297:Male; D017921:Mastadenovirus / Q000276:immunology*; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D009205:Myocarditis / Q000276:immunology* / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D014779:Virus Replication
chemical_list: D017252:CD3 Complex; D007371:Interferon-gamma