title: Coordinated regulation and widespread cellular expression of interferon-stimulated genes (ISG) ISG-49, ISG-54, and ISG-56 in the central nervous system after infection with distinct viruses.
abstract: The interferon (IFN)-stimulated genes (ISGs) ISG-49, ISG-54, and ISG-56 are highly responsive to viral infection, yet the regulation and function of these genes in vivo are unknown. We examined the simultaneous regulation of these ISGs in the brains of mice during infection with either lymphocytic choriomeningitis virus (LCMV) or West Nile virus (WNV). Expression of the ISG-49 and ISG-56 genes increased significantly during LCMV infection, being widespread and localized predominantly to common as well as distinct neuronal populations. Expression of the ISG-54 gene also increased but to lower levels and with a more restricted distribution. Although expression of the ISG-49, ISG-54, and ISG-56 genes was increased in the brains of LCMV-infected STAT1 and STAT2 knockout (KO) mice, this was blunted, delayed, and restricted to the choroid plexus, meninges, and endothelium. ISG-56 protein was regulated in parallel with the corresponding RNA transcript in the brain during LCMV infection in wild-type and STAT KO mice. Similar changes in ISG-49, ISG-54, and ISG-56 RNA levels and ISG-56 protein levels were observed in the brains of wild-type mice following infection with WNV. Thus, the ISG-49, ISG-54, and ISG-56 genes are coordinately upregulated in the brain during LCMV and WNV infection; this upregulation, in the case of LCMV, was totally (neurons) or partially (non-neurons) dependent on the IFN-signaling molecules STAT1 and STAT2. These findings suggest a dominant role for the ISG-49, ISG-54, and ISG-56 genes in the host response to different viruses in the central nervous system, where, particularly in neurons, these genes may have nonredundant functions.
authors.affiliation: School of Molecular and Microbial Biosciences, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Christie
authors.initials: C
authors.lastname: Wacher
authors.forename: Marcus
authors.initials: M
authors.lastname: Müller
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Hofer
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Getts
authors.forename: Regina
authors.initials: R
authors.lastname: Zabaras
authors.forename: Shalina S
authors.initials: SS
authors.lastname: Ousman
authors.forename: Fulvia
authors.initials: F
authors.lastname: Terenzi
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
authors.forename: Nicholas J C
authors.initials: NJ
authors.lastname: King
authors.forename: Iain L
authors.initials: IL
authors.lastname: Campbell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020805:Central Nervous System Viral Diseases / Q000276:immunology / Q000821:virology; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000472:pathogenicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014901:West Nile Fever / Q000276:immunology / Q000821:virology; D014902:West Nile virus / Q000472:pathogenicity*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C092573:Ifit1 protein, mouse; C092572:Ifit2 protein, mouse; C087697:Ifit3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor