Type I interferon shapes the distribution and tropism of tick-borne flavivirus

Several Flaviviruses are neurotropic and can cause encephalitis with significant long-term neurological sequelae. Viral tropism within the brain and the role(s) of vertebrate immunity in neurological disease is important to understand. We combined multimodal imaging (cm-nm scale) with single nuclei RNA-sequencing to study Langat virus in wildtype (WT) and IFN alpha/beta receptor knockout (Ifnar−/–) mice to visualize viral pathogenesis and define molecular mechanisms. Whole brain viral infection was imaged by Optical Projection Tomography coregistered to ex vivo MRI. Infection was limited to gray matter of olfactory, visual and somatosensory systems in WT mice, but extended into white matter, meninges and choroid plexus in Ifnar–/– mice. All cell types in Ifnar–/– animals displayed strong proinflammatory and IFN-I-independent response, likely due to infiltration of Ifng-expressing CD8+NK cells, whereas in WT this was tightly controlled. Multimodal imaging-transcriptomics demonstrations that control of innate immunity is a critical factor in pathogenesis.