Interferon-induced Ifit2/ISG54 protects mice from lethal VSV neuropathogenesis

Volker Fensterl, Jaime L. Wetzel, Srividya Ramachandran, Tomoaki Ogino, Stephen A. Stohlman, Cornelia C. Bergmann, Michael S. Diamond, Herbert W. Virgin, Ganes C. Sen

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108 Scopus citations

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.

Original languageEnglish
Article numbere1002712
JournalPLoS pathogens
Volume8
Issue number5
DOIs
StatePublished - May 1 2012

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    Fensterl, V., Wetzel, J. L., Ramachandran, S., Ogino, T., Stohlman, S. A., Bergmann, C. C., Diamond, M. S., Virgin, H. W., & Sen, G. C. (2012). Interferon-induced Ifit2/ISG54 protects mice from lethal VSV neuropathogenesis. PLoS pathogens, 8(5), [e1002712]. https://doi.org/10.1371/journal.ppat.1002712