Beschreibung:
<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background</jats:title>
<jats:p>Theiler’s murine encephalomyelitis virus (TMEV) is a single-stranded RNA virus that causes encephalitis followed by chronic demyelination in SJL mice and spontaneous seizures in C57BL/6 mice. Since earlier studies indicated a critical role of type I interferon (IFN-I) signaling in the control of viral replication in the central nervous system (CNS), mouse strain-specific differences in pathways induced by the IFN-I receptor (IFNAR) might determine the outcome of TMEV infection.</jats:p>
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<jats:title>Methods</jats:title>
<jats:p>Data of RNA-seq analysis and immunohistochemistry were used to compare the gene and protein expression of IFN-I signaling pathway members between mock- and TMEV-infected SJL and C57BL/6 mice at 4, 7 and 14 days post-infection (dpi). To address the impact of IFNAR signaling in selected brain-resident cell types, conditional knockout mice with an IFNAR deficiency in cells of the neuroectodermal lineage (NesCre<jats:sup>±</jats:sup>IFNAR<jats:sup>fl/fl</jats:sup>), neurons (Syn1Cre<jats:sup>±</jats:sup>IFNAR<jats:sup>fl/fl</jats:sup>), astrocytes (GFAPCre<jats:sup>±</jats:sup>IFNAR<jats:sup>fl/fl</jats:sup>), and microglia (Sall1Cre<jats:sup>ER±</jats:sup>IFNAR<jats:sup>fl/fl</jats:sup>) on a C57BL/6 background were tested. PCR and an immunoassay were used to quantify TMEV RNA and cytokine and chemokine expression in their brain at 4 dpi.</jats:p>
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<jats:title>Results</jats:title>
<jats:p>RNA-seq analysis revealed upregulation of most ISGs in SJL and C57BL/6 mice, but <jats:italic>Ifi202b</jats:italic> mRNA transcripts were only increased in SJL and <jats:italic>Trim12a</jats:italic> only in C57BL/6 mice. Immunohistochemistry showed minor differences in ISG expression (ISG15, OAS, PKR) between both mouse strains. While all immunocompetent Cre-negative control mice and the majority of mice with IFNAR deficiency in neurons or microglia survived until 14 dpi, lack of IFNAR expression in all cells (IFNAR<jats:sup>−/−</jats:sup>), neuroectodermal cells, or astrocytes induced lethal disease in most of the analyzed mice, which was associated with unrestricted viral replication. NesCre<jats:sup>±</jats:sup>IFNAR<jats:sup>fl/fl</jats:sup> mice showed more <jats:italic>Ifnb1</jats:italic>, <jats:italic>Tnfa</jats:italic>, <jats:italic>Il6</jats:italic>, <jats:italic>Il10</jats:italic>, <jats:italic>Il12b</jats:italic> and <jats:italic>Ifng</jats:italic> mRNA transcripts than Cre<jats:sup>−/−</jats:sup>IFNAR<jats:sup>fl/fl</jats:sup> mice. IFNAR<jats:sup>−/−</jats:sup> mice also demonstrated increased IFN-α, IFN-β, IL1-β, IL-6, and CXCL-1 protein levels, which highly correlated with viral load.</jats:p>
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<jats:title>Conclusions</jats:title>
<jats:p><jats:italic>Ifi202b</jats:italic> and <jats:italic>Trim12a</jats:italic> expression levels likely contribute to mouse strain-specific susceptibility to TMEV-induced CNS lesions. Restriction of viral replication is strongly dependent on IFNAR signaling of neuroectodermal cells, which also controls the expression of key pro- and anti-inflammatory cytokines during viral brain infection.</jats:p>
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