Abstract
Viral infections of the central nervous system cause acute or delayed neuropathology and clinical consequences ranging from asymptomatic courses to chronic, debilitating diseases. The outcome of viral encephalitis is partially determined by genetically programed immune response patterns of the host. Experimental infection of mice with Theiler's murine encephalomyelitis virus (TMEV) causes diverse neurologic diseases, including TMEV‐induced demyelinating disease (TMEV‐IDD), depending on the used mouse strain. The aim of the present study was to compare initial transcriptomic changes occurring in the brain of TMEV‐infected SJL (TMEV‐IDD susceptible) and C57BL/6 (TMEV‐IDD resistant) mice. Animals were infected with TMEV and sacrificed 4, 7, or 14 days post infection. RNA was isolated from brain tissue and analyzed by whole‐transcriptome sequencing. Selected differences were confirmed on a protein level by immunohistochemistry. In mock‐infected SJL and C57BL/6 mice, >200 differentially expressed genes (DEGs) were detected. Following TMEV‐infection, the number of DEGs increased to >700. Infected C57BL/6 mice showed a higher expression of transcripts related to antigen presentation via major histocompatibility complex (MHC) I, innate antiviral immune responses and cytotoxicity, compared with infected SJL animals. Expression of many of those genes was weaker or delayed in SJL mice, associated with a failure of viral clearance in this mouse strain. SJL mice showed prolonged elevation of MHC II and chemotactic genes compared with C57BL/6 mice, which presumably facilitates the induction of chronic demyelinating disease. In addition, elevated expression of several genes associated with immunomodulatory or –suppressive functions was observed in SJL mice. The exploratory study confirms previous observations in the model and provides an extensive list of new immunologic parameters potentially contributing to different outcomes of viral encephalitis in two mouse strains.
Highlights
A previous study in the Theiler's murine encephalomyelitis virus (TMEV) model showed up to 50% lower natural killer (NK) cell activity in the spleen of SJL compared with TMEV-IDD-resistant C57BL/10 (B10) mice, which correlated with significantly higher viral titers in the central nervous system (CNS) at 8 to 12 dpi [59]
We found a higher expression of tripartite motif-containing 12A (Trim12a), Trim12c, Trim30c, and Trim30d in B6 mice compared with SJL mice already under noninfectious conditions, and the difference increased even further upon TMEV-infection
Many genes involved in innate antiviral immune response showed a higher expression in TMEV- infected B6 mice, compared with TMEV-infected SJL mice, and differences were prominent during onset of the acute polioencephalitis (4 dpi)
Summary
Female SJL/JHanHsd (SJL) and C57BL/6JOlaHsd (B6) mice were purchased from Harlan Winkelmann, Borchen, Germany. A pairwise comparison of gene expression in SJL and B6 mice was performed for each condition (mock and TMEV), and timepoint following TMEV infection (4, 7, and 14 dpi) to detect which genes showed the highest absolute differences between strains. Read counts served as input to DESeq2 [54], and the list of differentially expressed genes (DEGs) was filtered with an absolute log2fold change (FC) cut-off of at least 1.5 and a p-value cut- off, corrected for multiple testing, of at most 0.05. In addition to pairwise comparisons between SJL and B6 mice, a time course analysis was performed employing the likelihood ratio test from the DESeq package in R (cut-off of p < 0.01) to detect strain- specific effects of TMEV-infection on gene expression over time. Overrepresented gene ontology (GO) terms in the category biological process were determined for DEG sets with a minimum of three genes for a category, and an FDR cut-off of
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