Memory Impairment Induced by Borna Disease Virus 1 Infection is Associated with Reduced H3K9 Acetylation

Background/Aims: Borna disease virus 1 (BoDV-1) infection induces cognitive impairment in rodents. Emerging evidence has demonstrated that Chromatin remodeling through histone acetylation can regulate cognitive function. In the present study, we investigated the epigenetic regulation of chromatin that underlies BoDV-1-induced cognitive changes in the hippocampus. Methods: Immunofluorescence assay was applied to detect BoDV-1 infection in hippocampal neurons and Sprague-Dawley rats models. The histone acetylation levels both in vivo and vitro were assessed by western blots. The acetylation-regulated genes were identified by ChIP-seq and verified by RT-qPCR. Cognitive functions were evaluated with Morris Water Maze test. In addition, Golgi staining, and electrophysiology were used to study changes in synaptic structure and function. Results: BoDV-1 infection of hippocampal neurons significantly decreased H3K9 histone acetylation level and inhibited transcription of several synaptic genes, including postsynaptic density 95 (PSD95) and brain-derived neurotrophic factor (BDNF). Furthermore, BoDV-1 infection of Sprague Dawley rats disrupted synaptic plasticity and caused spatial memory impairment. These rats also exhibited dysregulated hippocampal H3K9 acetylation and decreased PSD95 and BDNF protein expression. Treatment with the HDAC inhibitor, suberanilohydroxamic acid (SAHA), attenuated the negative effects of BoDV-1. Conclusion: Our results demonstrate that regulation of H3K9 histone acetylation may play an important role in BoDV-1-induced memory impairment, whereas SAHA may confer protection against BoDV-1-induced cognitive impairments. This study finds important mechanism of BoDV-1 infection disturbing neuronal synaptic plasticity and inducing cognitive dysfunction from the perspective of histone modification.

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Borna Disease Virus Infection Impairs Synaptic Plasticity

Journal of Virology ◽

10.1128/jvi.00612-07 ◽

2007 ◽

Vol 81 (16) ◽

pp. 8833-8837 ◽

Cited By ~ 20

Author(s):

Romain Volmer ◽

Christine M. A. Prat ◽

Gwendal Le Masson ◽

André Garenne ◽

Daniel Gonzalez-Dunia

Keyword(s):

Synaptic Plasticity ◽

Disease Virus ◽

Network Activity ◽

Multielectrode Arrays ◽

Neuronal Function ◽

Borna Disease Virus ◽

Electrophysiological Properties ◽

Neuronal Network Activity ◽

Activity Dependent ◽

Borna Disease

ABSTRACT The mechanisms whereby Borna disease virus (BDV) can impair neuronal function and lead to neurobehavioral disease are not well understood. To analyze the electrophysiological properties of neurons infected with BDV, we used cultures of neurons grown on multielectrode arrays, allowing a real-time monitoring of the electrical activity across the network shaped by synaptic transmission. Although infection did not affect spontaneous neuronal activity, it selectively blocked activity-dependent enhancement of neuronal network activity, one form of synaptic plasticity thought to be important for learning and memory. These findings highlight the original mechanism of the neuronal dysfunction caused by noncytolytic infection with BDV.

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Borna Disease Virus Glycoprotein Is Required for Viral Dissemination in Neurons

Journal of Virology ◽

10.1128/jvi.77.22.12222-12231.2003 ◽

2003 ◽

Vol 77 (22) ◽

pp. 12222-12231 ◽

Cited By ~ 38

Author(s):

Jeffrey J. Bajramovic ◽

Sylvia Münter ◽

Sylvie Syan ◽

Ulf Nehrbass ◽

Michel Brahic ◽

...

Keyword(s):

Disease Virus ◽

Hippocampal Neurons ◽

Neutralizing Antibodies ◽

Rna Virus ◽

Primary Cultures ◽

Viral Envelope ◽

Borna Disease Virus ◽

Viral Particles ◽

Borna Disease

ABSTRACT Borna disease virus (BDV) is a nonsegmented negative-strand RNA virus with a tropism for neurons. Infection with BDV causes neurological diseases in a wide variety of animal species. Although it is known that the virus spreads from neuron to neuron, assembled viral particles have never been visualized in the brains of infected animals. This has led to the hypothesis that BDV spreads as nonenveloped ribonucleoproteins (RNP) rather than as enveloped viral particles. We assessed whether the viral envelope glycoprotein (GP) is required for neuronal dissemination of BDV by using primary cultures of rat hippocampal neurons. We show that upon in vitro infection, BDV replicated and spread efficiently in this system. Despite rapid virus dissemination, very few infectious viral particles were detectable in the culture. However, neutralizing antibodies directed against BDV-GP inhibited BDV spread. In addition, interference with BDV-GP processing by inhibiting furin-mediated cleavage of the glycoprotein blocked virus spread. Finally, antisense treatment with peptide nucleic acids directed against BDV-GP mRNA inhibited BDV dissemination, marking BDV-GP as an attractive target for antiviral therapy against BDV. Together, our results demonstrate that the expression and correct processing of BDV-GP are necessary for BDV dissemination in primary cultures of rat hippocampal neurons, arguing against the hypothesis that the virus spreads from neuron to neuron in the form of nonenveloped RNP.

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Borna Disease Virus Phosphoprotein Modulates Epigenetic Signaling in Neurons To Control Viral Replication

Journal of Virology ◽

10.1128/jvi.00454-15 ◽

2015 ◽

Vol 89 (11) ◽

pp. 5996-6008 ◽

Cited By ~ 16

Author(s):

Emilie M. Bonnaud ◽

Marion Szelechowski ◽

Alexandre Bétourné ◽

Charlotte Foret ◽

Anne Thouard ◽

...

Keyword(s):

Viral Replication ◽

Histone Acetylation ◽

Host Cell ◽

Disease Virus ◽

Histone Acetyltransferase ◽

Cell Interaction ◽

Epigenetic Changes ◽

Borna Disease Virus ◽

Infected Cells ◽

Borna Disease

ABSTRACTUnderstanding the modalities of interaction of neurotropic viruses with their target cells represents a major challenge that may improve our knowledge of many human neurological disorders for which viral origin is suspected. Borna disease virus (BDV) represents an ideal model to analyze the molecular mechanisms of viral persistence in neurons and its consequences for neuronal homeostasis. It is now established that BDV ensures its long-term maintenance in infected cells through a stable interaction of viral components with the host cell chromatin, in particular, with core histones. This has led to our hypothesis that such an interaction may trigger epigenetic changes in the host cell. Here, we focused on histone acetylation, which plays key roles in epigenetic regulation of gene expression, notably for neurons. We performed a comparative analysis of histone acetylation patterns of neurons infected or not infected by BDV, which revealed that infection decreases histone acetylation on selected lysine residues. We showed that the BDV phosphoprotein (P) is responsible for these perturbations, even when it is expressed alone independently of the viral context, and that this action depends on its phosphorylation by protein kinase C. We also demonstrated that BDV P inhibits cellular histone acetyltransferase activities. Finally, by pharmacologically manipulating cellular acetylation levels, we observed that inhibiting cellular acetyl transferases reduces viral replication in cell culture. Our findings reveal that manipulation of cellular epigenetics by BDV could be a means to modulate viral replication and thus illustrate a fascinating example of virus-host cell interaction.IMPORTANCEPersistent DNA viruses often subvert the mechanisms that regulate cellular chromatin dynamics, thereby benefitting from the resulting epigenetic changes to create a favorable milieu for their latent and persistent states. Here, we reasoned that Borna disease virus (BDV), the only RNA virus known to durably persist in the nucleus of infected cells, notably neurons, might employ a similar mechanism. In this study, we uncovered a novel modality of virus-cell interaction in which BDV phosphoprotein inhibits cellular histone acetylation by interfering with histone acetyltransferase activities. Manipulation of cellular histone acetylation is accompanied by a modulation of viral replication, revealing a perfect adaptation of this “ancient” virus to its host that may favor neuronal persistence and limit cellular damage.

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