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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Interferon-induced Ifit2/ISG54 protects mice from lethal VSV neuropathogenesis
Volker Fensterl1, Jaime L Wetzel, Srividya Ramachandran
1Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Plos Pathogens
|May 23, 2012
Summary
Interferon-induced gene Ifit2 is crucial for protecting mice against lethal vesicular stomatitis virus (VSV) brain infections. Lacking Ifit2 makes mice susceptible to VSV, highlighting its specific antiviral role in the central nervous system.
Area of Science:
- Immunology
- Virology
- Genetics
Background:
- Interferon (IFN) protects against viral infections, but the specific roles of individual interferon-stimulated genes (ISGs) remain unclear.
- The interferon-induced with tetratricopeptide repeats (Ifit) gene family, including Ifit1, Ifit2, and Ifit3, are prominent ISGs induced during viral infections.
- While Ifit genes are upregulated in the mouse central nervous system (CNS) after intranasal vesicular stomatitis virus (VSV) infection, their specific contributions to antiviral defense are not well-defined.
Purpose of the Study:
- To investigate the specific antiviral functions of Ifit1 and Ifit2 in the context of VSV infection in mice.
- To determine the contribution of Ifit2 to protection against VSV pathogenesis, particularly within the central nervous system.
- To elucidate the tissue- and virus-specific antiviral actions mediated by interferon-stimulated genes.
Main Methods:
- Generation and utilization of knockout mice lacking either Ifit1 or Ifit2.
- Intranasal and intracranial inoculation of wild-type, Ifit1(-/-), and Ifit2(-/-) mice with VSV.
- Monitoring of clinical signs, survival rates, viral titers in various organs (CNS, lung, liver), and viral tropism in the brain.
Main Results:
- Ifit2 knockout (Ifit2(-/-)) mice exhibited uniformly lethal outcomes following intranasal VSV infection, characterized by severe neurological symptoms.
- Wild-type and Ifit1(-/-) mice were largely protected from VSV pathogenesis, surviving infection without significant disease.
- While intracranial VSV injection showed no significant difference in replication or survival between wild-type and Ifit2(-/-) mice, intranasal infection led to significantly higher VSV titers in the brains of Ifit2(-/-) mice as the infection progressed, despite equivalent initial replication in olfactory bulbs and selective neuronal tropism.
Conclusions:
- The interferon-stimulated gene Ifit2 plays a critical, tissue-specific role in antiviral defense against VSV within the mouse central nervous system.
- Ifit2 is essential for protection against lethal VSV encephalitis following intranasal infection, demonstrating a clear antiviral mechanism mediated by this ISG.
- This study highlights the virus- and tissue-specific nature of interferon-mediated antiviral immunity, underscoring the distinct functions of individual ISGs.
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