Tumor necrosis factor-α receptor 1 mediates BoDV1-driven changes in mitochondrial and peroxisomal dynamics in neurons

Abstract

Borna disease virus 1 (BoDV1) causes persistent infection in the mammalian brain, characterized by glial activation and T cell-mediated immunopathological neuroinflammation in susceptible end hosts. Peroxisomes and mitochondria play essential roles in cellular antiviral immune response, but the effect of BoDV1 infection on peroxisomal and mitochondrial dynamics and their main antioxidant enzymes was still not clear. This study used different mouse lines – i.e. tumor necrosis factor-α transgenic (TNFTg), TNF receptor-1 knockout (TNFR1ko), and TNFR2ko mice in comparison to wild-type (Wt) mice – in a model where 42-day-old non-infected mice were compared to respective BoDV1-infected mice and the other mouse lines. In the TNFTg mouse line, moderate overexpression of TNF-α in the forebrain regions creates a proinflammatory state, mimicking chronic inflammation. Focusing on the hippocampus, cerebral and cerebellar cortices, the abundances of peroxisomes and mitochondria alongside their main antioxidant enzymes, catalase and superoxide dismutase 2 (SOD2), respectively, were analyzed in several distinct neuronal cell types of each mouse line, with or without BoDV1 infection. In non-infected Wt mice, mitochondrial but not peroxisomal abundances were highest in cerebral pyramidal neurons and cerebellar Purkinje neurons. In non-infected TNFTg mice, a strong increase in mitochondrial (6.9-fold) and SOD2 (12.1-fold) abundances was detected; peroxisomal abundance increased slightly (1.5-fold), but that of catalase decreased (2.9-fold). Unlike in non-infected TNFR1ko (where no changes occurred), the abundances of both subcellular organelles, but not of their antioxidant enzymes, increased in non-infected TNFR2ko mice. Following BoDV1 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 seen in Wt and TNFR2ko mice. Little or no changes occurred in BoDV1-infected TNFR1ko mice. Chronic TNF-α overexpression in TNFTg mice hampered changes in peroxisome and catalase abundances after BoDV1 infection, but not that of mitochondria and SOD2. The findings of this study suggest that the TNF system is involved in the biogenesis of peroxisomes and mitochondria. Moreover, TNFR1 signaling mediated the BoDV1-induced alterations of both organelles and the availability of their main antioxidant enzymes, highlighting new mechanisms by which BoDV1 could evade the innate immune system and achieve viral persistence.