title: The type I interferon system protects mice from Semliki Forest virus by preventing widespread virus dissemination in extraneural tissues, but does not mediate the restricted replication of avirulent virus in central nervous system neurons.
abstract: Semliki Forest virus (SFV) infection of the mouse provides a powerful model to study the pathogenesis of virus encephalitis. SFV and other alphavirus-based vector systems are increasingly used in biotechnology and medicine. This study analysed the strong susceptibility of this virus to type I interferon (IFN) responses. Following intraperitoneal infection of adult mice, SFV strain A7(74) was efficiently (100 %) neuroinvasive. In contrast, SFV4 was poorly (21 %) neuroinvasive. Upon entry into the brain, both viruses activated type I IFN responses. As determined by quantitative RT-PCR, activation of the IFN-alpha gene was proportional to virus RNA load. An intact type I IFN system was required for protection against both strains of SFV. IFN strongly curtailed virus spread in many cell types and in many tissues. In mice with an intact type I IFN system, infected cells were rarely observed and tissue tropism was difficult to determine. In the absence of a functional type I IFN system, the tropism and the potential for rapid and widespread infection of this virus was revealed. Virus infection was readily observed in the myocardium, endocardium, exocrine pancreas, adipose tissue, smooth muscle cells and in the brain in meningeal cells, ependymal cells and oligodendrocytes. In the brains of mice with and without type I IFN responses, virus infection of neurons remained rare and focal, indicating that the previously described restricted replication of SFV A7(74) in neurons is not mediated by type I IFN responses.
authors.affiliation: Virology, Centre for Infectious Diseases, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH19 1QH, UK.
authors.forename: Rennos
authors.initials: R
authors.lastname: Fragkoudis
authors.affiliation: Virology, Centre for Infectious Diseases, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH19 1QH, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Breakwell
authors.affiliation: Virology, Centre for Infectious Diseases, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH19 1QH, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: McKimmie
authors.affiliation: Virology, Centre for Infectious Diseases, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH19 1QH, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Boyd
authors.affiliation: Virology, Centre for Infectious Diseases, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH19 1QH, UK.
authors.forename: Gerald
authors.initials: G
authors.lastname: Barry
authors.affiliation: Virology, Centre for Infectious Diseases, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH19 1QH, UK.
authors.forename: Alain
authors.initials: A
authors.lastname: Kohl
authors.affiliation: Institute of Technology, University of Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Merits
authors.affiliation: Virology, Centre for Infectious Diseases, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH19 1QH, UK.
authors.forename: John K
authors.initials: JK
authors.lastname: Fazakerley
mesh_terms: D018354:Alphavirus Infections / Q000276:immunology* / Q000821:virology*; D000818:Animals; D002490:Central Nervous System / Q000276:immunology / Q000821:virology; D005796:Genes / Q000235:genetics; D007370:Interferon Type I / Q000235:genetics / Q000302:isolation & purification*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009474:Neurons / Q000821:virology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012672:Semliki forest virus / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*; D019562:Viral Load; D014774:Virulence
chemical_list: D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta