Project description:Theiler’s murine encephalomyelitis virus (TMEV) induces different diseases in the central nervous system (CNS) and heart, depending on the mouse strains and time course, where cytokines play a key role for viral clearance and immune-mediated pathology (immunopathology). In SJL/J mice, TMEV infection causes chronic TMEV-induced demyelinating disease (TMEV-IDD) in the spinal cord around 1 month post infection (p.i.). Unlike other immunopathology models, both pro-inflammatory and anti-inflammatory cytokines can play dual roles in TMEV-IDD. Pro-inflammatory cytokines play a beneficial role in viral clearance while they also play a detrimental role in immune-mediated demyelination. Anti-inflammatory cytokines suppress not only protective anti-viral immune responses but also detrimental autoreactive immune responses. On the other hand, in C3H mice, TMEV infection induces a non-CNS disease, myocarditis, with three phases: phase I, viral pathology with interferon and chemokine responses; phase II, immunopathology mediated by acquired immune responses; and phase III, cardiac fibrosis. Although the precise mechanism how a single virus, TMEV, induces the distinct diseases in different organs is unclear, principal component analysis (PCA) of transcriptome data allows us to identify the key factors contributing to distinct immunopathology. The PCA demonstrated that in vitro infection of a cardiomyocyte cell line could reproduce the transcriptome profile of phase I in TMEV-induced myocarditis; distinct interferon/chemokine-related responses were induced in vitro in infected cardiomyocytes, but not in infected neuronal cells. In addition, the PCA of in vivo CNS transcriptome data showed that decreased lymphatic marker expression was associated with inflammation in TMEV infection. Here, dysfunction of lymphatic vessels may contribute to immunopathology by delaying clearance of cytokines and immune cells from the inflammatory site, although this might confine the virus at the site, preventing virus spread via lymphatic vessels. On the other hand, in the heart, dysfunction of lymphatics was associated with reduced lymphatic muscle contractility by pro-inflammatory cytokines. Therefore, TMEV infection could induce different cytokine expressions as well as lymphatic vessel dysfunction by the distinct mechanism between the CNS and heart, which might contribute to organ-specific immunopathology.

Project description: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 programmed 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 intracerebrally with TMEV and sacrificed 4, 7 or 14 days post infection (dpi). Control animals of both strains were inoculated with vehicle only and sacrificed at 7 dpi. 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 mice 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 MHCI I, innate antiviral immune responses and cytotoxicity, compared to infected SJL animals. Many of those genes were also upregulated in SJL mice upon infection, but the response was weaker or delayed, which could be responsible for failure of viral clearance in this mouse strain. SJL mice showed prolonged elevation of MHC II and chemotactic genes, compared to 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 immunologic parameters potentially contributing to different outcomes of viral encephalitis in two mouse strains.

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Immunological role of platelets in Theiler’s virus-induced inflammatory demyelinating disease and myocarditis

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