A genetically encoded reporter reveals coordinated interferon responses in neurons and non-neuronal cells in the brain

Abstract Interferons (IFNs) are canonical antiviral cytokines with emerging homeostatic functions across tissues, including in the brain. However, detecting IFN-responsive cells remains challenging, particularly in the immune-restricted brain environment, limiting our understanding of the full breadth of IFN signaling across diverse cell types. Here we developed a novel mouse reporter that detects IFN responses in the brain and peripheral tissues, including in neurons. This tool, IFN-brite, Bright Reporter of Interferon sTimulated gene Expression, has two copies of the fluorophore mGreenLantern downstream of the native Isg15 IFN response gene. We observed IFN responses across multiple cell lineages. Deletion of the Type I interferon receptor Ifnar1 largely abrogated these responses, including to IFNγ, suggesting that Type II signaling can trigger secondary Type I responses. We observed IFN-responsive cells including neurons in a model of ischemic stroke and during experience-dependent neural plasticity. Furthermore, we found that peripheral infection with Sars-CoV2 but not influenza A leads to IFN-responsive neurons in the brain, suggesting differential impacts of these two pathogens in the nervous system. These data define a broadly useful new tool for studying IFN responsive cells and provide evidence that diverse cell types including neurons can respond to IFNs. Competing Interest Statement The authors have declared no competing interest. Footnotes ‡ National Center for Biomodels, National Institutes of Applied Research, Taipei, Taiwan. This current version has more characterization of the reporter mouse, including neuronal expression patterns (Figure 2), comparisons to an existing reporter line (Figure 2), validation of IFN-I responses by global receptor knockout (Figure 3), and reporter activity after ischemic stroke (Figure 4) and SARS-CoV-2 (Figure 6). Authors updated. Supplemental figures updated.