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

Abstract

Summary Borna disease viruses (BoDV) have recently emerged as zoonotic neurotropic pathogens. These persistent RNA viruses assemble nuclear replication centers (vSPOT) in close 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.

Borna disease virus 1 impairs DNA double-strand break repair through the ATR/Chk1 signalling pathway, resulting in learning and memory impairment in rats

“…Marty et al . [36] reported that BoDV-1 infection increases primary neuronal DSB levels, which is consistent with our results. However, this study extends those findings by reporting that BoDV-1 infection causes neuronal accumulation of DSBs in vivo in laboratory animals.…”

“…Two pieces of evidence support an increase in the number of DSBs: (i) high levels of distinct nuclear foci immunoreactive for γ-H 2 AX [31,32], which is a well-established marker of DSBs, and (ii) upregulated comet tail moment in single cells in comet assays performed at neutral pH [33]. Marty et al [36] reported that BoDV-1 infection increases primary neuronal DSB levels, which is consistent with our results. However, this study extends those findings by reporting that BoDV-1 infection causes neuronal accumulation of DSBs in vivo in laboratory animals.…”

“…However, this study extends those findings by reporting that BoDV-1 infection causes neuronal accumulation of DSBs in vivo in laboratory animals. In addition, Marty et al [36] showed that not only BoDV-1 infection but also its major proteins, the nucleoprotein and/or its phosphoprotein, were alone causing neuronal DSBs which co-localized with BoDV-1 replication factories in the nucleus. Either N-or P-protein alone increased γ-H 2 AX levels in neurons by 50 %.…”

Chronic IL-1-induced DNA double-strand break response in hippocampal neurons drives cognitive deficits

“…4A). As shown previously 55,58 , we confirmed using confocal immunofluorescence microscopy that mature neurons express diffuse 53BP1 staining in their nuclei (Fig. 4Ai , ii & Extended Data Fig.…”

Borna Disease Virus 1 Phosphoprotein Forms a Tetramer and Interacts with Host Factors Involved in DNA Double-Strand Break Repair and mRNA Processing

“…The genome of bornaviriruses consists of approximately 8900 nucleotides and represents the smallest known genome amongst Mononegavirales. BoDV-1 vSPOTs formed by P protein-driven liquid-liquid phase separation [48], are present in the nucleus, in close interaction with the chromatin, where they dock on neuronal DNA double-strand breaks (DSBs), thereby affecting neuronal epigenetics and activity [49]. In particular, both N and P seem to modulate epigenetic signalling in neurons [50,51].…”