Borna disease virus docks on neuronal DNA double-strand breaks to replicate and dampens neuronal activity

Borna disease viruses (BoDV), which have emerged as zoonotic neurotropic pathogens, exhibit persistent RNA characteristics and form nuclear replication centers (vSPOT) closely interacting with the host chromatin. Despite this interaction, the exact nature of its topology and the resulting impact on neuronal function remain unexplored. Within neurons, the discovery of DNA double-strand breaks (DSB) has unveiled novel epigenetic mechanisms governing neurotransmission and cognition. These activity-dependent DSBs play a crucial role in neuronal plasticity, potentially affected during infection. This study demonstrates that BoDV-1 infection or the isolated expression of viral nucleoprotein and phosphoprotein elevates levels of neuronal DSBs. Intriguingly, inducing DSBs facilitates renewed recruitment of vSPOT, which co-localizes with DSBs, thereby enhancing viral RNA replication. Persistent BoDV-1 presence reduces neuronal activity and responsiveness to stimulation by diminishing the surface expression of glutamate receptors. In conclusion, the findings suggest a novel mechanistic interplay between RNA virus persistence and neuronal function, mediated through the regulation of DSB levels.
(LA)