Viral tropism and host responses in the brain

Neurotropic flaviviruses, including West Nile virus, Zika virus, and tick-borne encephalitis virus cause serious disease in people worldwide, and are particularly efficient in invading the brain. No treatment is available for any of them.

This project will employ state-of-the-art technologies which enable us to tackle the most complex phenomena in flavivirus infection: neuroinvasion, cellular tropism and viral clearance in the mammalian brain as well as identify host factors involved in replication.

To achieve this we will use viral genetics, single cell RNAseq, in vitro and in vivo models and imaging across 7 orders of magnitude from the cm to sub nm scales.

Using near-infrared optical projection tomography combined with scRNAseq we will map the viral infection in 3D in the entire mammalian brain, allowing precise identification of the viral entry point(s), how the innate immune system shape tropism, how different cells respond and the viral determinants of tropism.

Guided by this information we will provide a structural understanding of the macromolecular complex that sheltered virus replication i.e. viral factories, by developing a novel workflow to conduct 3D cryo-EM directly in infected brain samples. We will identify cellular requirements for viral replication which can be used as antiviral targets.

This will allow us to reach a mechanistic understanding of key phenomena infection biology and thereby identify new ways to combat flavivirus infection in mammalian brains.