title: Interferon-induced Ifit2/ISG54 protects mice from lethal VSV neuropathogenesis.
abstract: Interferon protects mice from vesicular stomatitis virus (VSV) infection and pathogenesis; however, it is not known which of the numerous interferon-stimulated genes (ISG) mediate the antiviral effect. A prominent family of ISGs is the interferon-induced with tetratricopeptide repeats (Ifit) genes comprising three members in mice, Ifit1/ISG56, Ifit2/ISG54 and Ifit3/ISG49. Intranasal infection with a low dose of VSV is not lethal to wild-type mice and all three Ifit genes are induced in the central nervous system of the infected mice. We tested their potential contributions to the observed protection of wild-type mice from VSV pathogenesis, by taking advantage of the newly generated knockout mice lacking either Ifit2 or Ifit1. We observed that in Ifit2 knockout (Ifit2(-/-)) mice, intranasal VSV infection was uniformly lethal and death was preceded by neurological signs, such as ataxia and hind limb paralysis. In contrast, wild-type and Ifit1(-/-) mice were highly protected and survived without developing such disease. However, when VSV was injected intracranially, virus replication and survival were not significantly different between wild-type and Ifit2(-/-) mice. When administered intranasally, VSV entered the central nervous system through the olfactory bulbs, where it replicated equivalently in wild-type and Ifit2(-/-) mice and induced interferon-β. However, as the infection spread to other regions of the brain, VSV titers rose several hundred folds higher in Ifit2(-/-) mice as compared to wild-type mice. This was not caused by a broadened cell tropism in the brains of Ifit2(-/-) mice, where VSV still replicated selectively in neurons. Surprisingly, this advantage for VSV replication in the brains of Ifit2(-/-) mice was not observed in other organs, such as lung and liver. Pathogenesis by another neurotropic RNA virus, encephalomyocarditis virus, was not enhanced in the brains of Ifit2(-/-) mice. Our study provides a clear demonstration of tissue-, virus- and ISG-specific antiviral action of interferon.
authors.affiliation: Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Volker
authors.initials: V
authors.lastname: Fensterl
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Wetzel
authors.forename: Srividya
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ogino
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Stohlman
authors.forename: Cornelia C
authors.initials: CC
authors.lastname: Bergmann
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001921:Brain / Q000821:virology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004686:Encephalomyocarditis virus / Q000276:immunology / Q000472:pathogenicity; D005260:Female; D016899:Interferon-beta / Q000378:metabolism; D008099:Liver / Q000821:virology; D008168:Lung / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D054243:Vesicular Stomatitis / Q000276:immunology* / Q000473:pathology / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology / Q000472:pathogenicity*; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C522692:ISG54 protein, mouse; C522693:ISG56 protein, mouse; C092573:Ifit1 protein, mouse; C092572:Ifit2 protein, mouse; D011506:Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D016899:Interferon-beta