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

Borna disease viruses (BoDV) have recently emerged as zoonotic neurotropic pathogens. These persistent RNA viruses assemble nuclear replication centers (vSPOT) in dose interaction with the host chromatin. However, the topology of this interaction and its consequences on neuronal function remain unexplored. In neurons, DNA double-strand breaks (DSB) have been identified as novel epigenetic mechanisms regulating neurotransmission and cognition. Activity-dependent DSB contribute critically to neuronal plasticity processes, which could be impaired upon infection. Here, we show that BoDV-1 infection, or the singled-out expression of viral Nucleoprotein and Phosphoprotein, increases neuronal DSB levels. Of interest, inducing DSB promoted the recruitment anew of vSPOT colocalized with DSB and increased viral RNA replication. BoDV-1 persistence decreased neuronal activity and response to stimulation by dampening the surface expression of glutamate receptors. Taken together, our results propose an original mechanistic cross talk between persistence of an RNA virus and neuronal function, through the control of DSB levels.

Automated summary

In this study, it was found that Borna disease virus infection or expression of viral nucleoprotein and phosphoprotein increased DNA double-strand break (DSB) levels in neurons. Inducing DSB promoted the recruitment of viral replication centers colocalized with DSB and enhanced viral RNA replication. BoDV-1 persistence decreased neuronal activity and response to stimulation by reducing the surface expression of glutamate receptors. These findings suggest a novel mechanistic cross talk between RNA virus persistence and neuronal function through the control of DSB levels.