Rubicon 2022 – Shirley Braspenning – Control of HSV-1 latency by RNA modifications

Project summary

Alphaherpesviruses, including herpes simplex virus type 1 (HSV-1), are increasingly linked to the development of neurodegenerative diseases because of their ability to establish life-long latency in the nervous system. Periodic viral reactivation is triggered by physiological and neurological stress, but the exact molecular mechanisms remain unclear.

Modification of mRNA, including methylation of adenosine at the N6 position (m6A) can dynamically alter gene expression in cellular transcriptomes, and thereby controls numerous biological processes. Lytic HSV-1 infection drastically changes the m6A modification landscape, but it is unclear how m6A modifications influence latency. In this proposal, I will elucidate the role of m6A modifications in the control of viral latency and reactivation. Using cultured primary neurons – a well-established model for HSV-1 latency – I will determine which m6A modification factors are crucial for latency and how m6A modifications influence neuronal resilience signalling. Next, I will combine this model with state-of-the-art sequencing techniques to interrogate which neuronal and viral mRNAs are differentially expressed and methylated during latency and reactivation, thereby identifying novel neuronal regulatory pathways that control latency.

In summary, in this fellowship proposal I will identify molecular switches controlling HSV-1 latency that could be attractive therapeutic targets to prevent viral reactivation and associated neurodegeneration.