Tumor necrosis factor-a receptor 1 mediates changes in mitochondrial and peroxisomal dynamics in neurons – a mechanism contributing to Borna disease virus 1 persistence in the brain

Abstract Borna disease virus 1 (BoDV-1) causes a persistent, non-cytolytic infection in the mammalian brain accompanied by glial activation and T-cell-mediated neuroinflammation in susceptible end hosts. Peroxisomes and mitochondria play essential roles in cellular antiviral immune response, but the effect of BoDV-1 infection on peroxisomal and mitochondrial dynamics and their respective antioxidant capacities is still not clear. Using different mouse lines – i.e. tumor necrosis factor-α transgenic (TNFTg; to mimic chronic inflammation), TNF receptor-1 knockout (TNFR1ko), and TNFR2ko mice in comparison to wild-type (Wt) mice – we analyzed the abundances of both organelles and their main antioxidant enzymes, catalase and superoxide dismutase 2 (SOD2), in neurons of the hippocampus, cerebral and cerebellar cortices. In non-infected TNFTg mice, we detected a strong increase in mitochondrial (6.9-fold) and SOD2 (12.1-fold) abundances; peroxisomal abundance increased slightly (1.5-fold), but that of catalase decreased (2.9-fold). Unlike in TNFR1ko where no changes occurred, the abundances of both organelles, but not of their antioxidant enzymes, increased in TNFR2Ko mice. After BoDV-1 infection, a strong decrease in mitochondrial (2.1-6.5-fold), SOD2 (2.7-9.1-fold), and catalase (2.7-10.3-fold) abundances, but a slight increase in peroxisomes (1.3-1.6-fold) were detected in Wt and TNFR2ko mice, whereas no changes occurred in TNFR1ko mice. Chronic TNF overexpression prevented changes in peroxisome and catalase abundances, but not that of mitochondria and SOD2. Our data suggest that the TNF system is involved in the biogenesis of both subcellular organelles. Moreover, TNFR1 signaling mediated the BoDV-1-induced alterations of both organelles and the availability of their main antioxidant enzymes, highlighting new mechanisms by which BoDV-1 could achieve immune evasion and viral persistence.