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Title

Antiviral Programs in the Brain

Date of Award

Spring 5-15-2013

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Although susceptibility of neurons in the brain to microbial infection is a major determinant of clinical outcome, little is known about the molecular factors governing this. Here, we show that two types of neurons from distinct brain regions exhibited differential permissivity to replication of several positive-stranded RNA viruses. Granule cell neurons (GCN) of the cerebellum and cortical neurons (CN) from the cerebral cortex have unique innate immune programs that confer differential susceptibility to viral infection ex vivo and in vivo. By transducing CN with genes that were expressed more highly in GCN, we identified three interferon-stimulated genes (ISGs; Ifi27, Irg1, and Rsad2/Viperin) that mediated antiviral effects against different neurotropic viruses. Moreover, we found that the epigenetic state and microRNA-mediated regulation of ISGs correlates with enhanced antiviral response in GCN. Thus, neurons from evolutionarily distinct brain regions have unique innate immune signatures, which likely contribute to their relative permissiveness to infection.

Previous studies have demonstrated that type I interferon (IFN) restricts West Nile virus (WNV) replication and pathogenesis in peripheral and central nervous system (CNS) tissues. However, the in vivo role against WNV infection of specific antiviral genes that are induced by IFN remains less well characterized. Here, using Ifit2-/- mice we defined the antiviral function of the interferon-stimulated gene (ISG) Ifit2 in limiting infection and disease in vivo by a virulent North American strain of WNV. Compared to congenic wild-type controls, Ifit2-/- mice infected with WNV subcutaneously or intracranially showed increased lethality and/or enhanced viral replication in a tissue-restricted manner. Virological analysis of cultured macrophages, dendritic cells, fibroblasts, cerebellar granule cell neurons, and cortical neurons revealed cell-type specific antiviral functions of Ifit2. In comparison, little effect of Ifit2 was observed on the induction or magnitude of innate or adaptive immune responses. Collectively, our results suggest that Ifit2 restricts WNV infection and pathogenesis in different tissues in a cell-intrinsic and cell-type specific manner.

Language

English (en)

Chair and Committee

Michael S Diamond

Committee Members

Michael Brent, David Wang, Herbert W Virgin, Marco Colonna, Joseph Dougherty

Comments

Permanent URL: https://doi.org/10.7936/K7N29TWT

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