Abstract
Differences in antiviral and inflammatory gene expression influence viral clearance in the central nervous system. Persistent antiviral and inflammatory gene expression are associated with neurodegeneration and the development of neurodiseases. Long non-coding RNAs (LncRNAs) are key cell-specific regulators of gene transcription and are differentially expressed in antiviral responses and neurodegenerative diseases. The purpose of this study was to explore the role of the novel lncRNA Nostrill in neuronal antiviral responses using in vivo and in vitro model systems. The mouse model Theiler’s Murine Encephalomyelitis Virus-Induced Demyelinating Disease (TMEV-IDD) is a preclinical model of Multiple Sclerosis (MS) and is used to assess mouse strains resistant and susceptible to the chronic IDD phase of the infection. Few studies have investigated the mechanisms of antiviral gene expression in TMEV-IDD resistant and susceptible mice during the acute phase of infection. Differences in lncRNA expression during the acute phase, when hippocampal neurons are the primary targets of TMEV infection, may account for the unique viral pathogenesis of TMEV-IDD resistant and susceptible mice. When neuronal viral infection is at its height during the acute phase of TMEV-IDD, expression of the novel lncRNA Nostrill was evaluated in TMEV-IDD resistant and susceptible mice. In vivo, TMEV-IDD resistant and TMEV-IDD susceptible mice upregulated Nostrill in the hippocampus while only TMEV-IDD susceptible mice significantly upregulated Nostrill in the cortex. Nostrill expression was localized to NeuN positive neurons in the hippocampus and cortex. NFkB p65-mediated antiviral gene transcription was upregulated by TMEV infection and was correlated with Nostrill expression. In vitro, knockdown studies in neuronal cell lines showed that Nostrill regulated NFkB p65-mediated gene transcription and knockdown of Nostrill increased TMEV viral burden. Mechanistic studies demonstrated that Nostrill translocates to the cytoplasm with TMEV infection and that NFkB p65 is required for Nostrill transcription. Nostrill physically interacts with NFkB p65 to promote occupancy of NFkB p65 and RNA polymerase II at the Irf7 promoter. Nostrill may play a regulatory role in neuronal NFkB p65-mediated antiviral gene transcription and may be a preventative target for neurodegenerative diseases.