Mechanisms of antiviral defense in the CNS - uncovered through patient-mimicking transgenic mice and human brain organoids

Viral infections can cause devastating diseases if not controlled by the immune system.

This includes diseases in the central nervous system (CNS) where e.g. herpes simplex virus 2 (HSV2) infection can lead to myelitis or meningitis. However, the mechanisms underlying viral CNS diseases remain unknown.

We recently identified a novel loss-of-function mutation in IKBKE in an HSV2 meningitis patient, and demonstrated it to be responsible for disease-susceptibility. We have now generated a transgenic mouse carrying this mutation. This represents a unique tool to decipher the mechanisms of CNS diseases caused by HSV2.

To approach this, we will perform deep characterization of the infectious and immunological phenotype of the IKKεF109X mice using well-established methods in infection immunology (e.g. disease scoring, virus assays, cytokine assay, and immunohistochemistry), and combine this with high-end single cell and spatial omics technologies.

Using brain organoids derived from the HSV2 meningitis patient, we will validate the human relevance of the findings.

The project is feasible, competitive, and can be completed within the timeframe, since we have 1) generated the IKKεF109X mouse line, 2) observed elevated susceptibility to HSV2 infection in the mice, and 3) implemented spatial transcriptomics and proteomics technologies.

This project will provide new understanding of the mechanism of HSV2-driven CNS disease – a requirement for design of novel treatments.