Abstract
Abstract The antiviral efficacy of Ifit2, an interferon-induced protein with tetratricopeptide repeats 2, is known for its ability to restrict the neurotropic murine-β-coronavirus, RSA59 infection. Intracranial injection of RSA59 in Ifit2 deficient (-/-) compared to wild-type (WT) mice results in impaired microglial activation and peripheral lymphocyte infiltration into the brain with severe morbidity and mortality in the acute phase of the disease. RSA59-infected Ifit2-/- mice also showed extensive viral replication, spreading throughout the spinal cord with impaired microglial activation and T-cell infiltration. Cervical-lymph-nodes of RSA59-infected Ifit2-/- mice exhibited reduced activation of CD4+ T cells and impaired IFNγ expression while preserving the blood-brain barrier integrity. To understand Ifit2's impact on the chronic demyelination phase, Ifit2-/- and Ifit2+/+ (WT) mice were observed for neuropathological outcomes upon RSA59 infection. The chronic disease phase in RSA59-infected Ifit2-/- mice demonstrated severe demyelination and persistent viral load. Furthermore, understanding molecular interactions in a reductionist approach using co-immunoprecipitation showed that upregulated Ifit2 in RSA59-infected primary astrocytes can interact with viral nucleocapsid protein. Thus, this study highlights that Ifit2's direct interaction with viral nucleocapsid protein can restrict RSA59 spread throughout the CNS in the acute phase, thus limiting severe chronic demyelination.
Published Version
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