Whole-brain fluorescence-MRI coregistration for precise anatomical mapping of virus infection

Neurotropic virus infections cause tremendous disease burden. Methods visualizing infection in the whole brain remain unavailable which greatly impedes understanding of viral neurotropism and pathogenesis. We devised an approach to visualize the distribution of neurotropic virus infection in whole mouse brain ex vivo. Optical projection tomography (OPT) signal was coregistered with a unique magnetic resonance imaging (MRI) brain template, enabling precise anatomical mapping of viral distribution, and the effect of type I interferon on distribution of infection was analyzed. Guided by OPT-MR, we show that Langat virus specifically targets sensory brain systems and the lack of type I interferon response results in an anatomical shift in infection patterns in the brain. We confirm this regional tropism, observed with whole brain OPT-MRI, by confocal and electron microscopy to provide unprecedented insight into viral neurotropism. This approach can be applied to any fluorescently labeled target in the brain.