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.

Crystal structure and nucleotide selectivity of human IFIT5/ISG58

“…ISG58 expression can be induced strongly upon viral infection [4], therefore, we sought to examine the potential inhibitory effect of ISG58 on viral replication by using a model of vesicular stomatitis virus expressing GFP (VSV-GFP). Earlier work reported that both ISG54 and ISG56 inhibited VSV replication when they were overexpressed in HEK293T cells [1,7]. Similarly, ISG58 reduced VSV replication by more than 60% ( Figure 1G).…”

The brain parenchyma has a type I interferon response that can limit virus spread

“…Previous studies have demonstrated that viral infection can stimulate expression of ISGs and proinflammatory cytokines in cultured CNS cells and in the brain (8,10,55,56) and that both neurons and glia are responsive to IFN treatment (57)(58)(59). Additionally, studies tracking virus spread into the brain from peripheral sites of inoculation have highlighted the importance of the innate immune response in preventing high virus load within the brain (14,50,60,61). However, there have been no studies that resolved whether an innate immune response mounted within the brain parenchyma can limit viral spread, especially along neuronal circuitry.…”

Zinc-finger antiviral protein mediates retinoic acid inducible gene I–like receptor-independent antiviral response to murine leukemia virus

“…Although type I IFN is essential for the protection of hosts from lethal infection with a variety of RNA viruses, such as influenza A virus (IAV) and vesicular stomatitis virus (VSV), type I IFN is not essential for induction of the antiviral state against MLV (16)(17)(18). Therefore, a different type of innate immune system has been proposed to protect hosts from MLV infection.…”