Bornavirus, neurones et épigénétique : un ''ménage à trois'' mutuellement salutaire ?

Bornavirus, neurons and epigenetics : a fruitful ''ménage à trois''?

• Auteur / Autrice : Emilie Bonnaud
• Direction : Cécile Malnou
• Type : Thèse de doctorat
• Discipline(s) : Microbiologie
• Date : Soutenance le 15/10/2015
• Etablissement(s) : Toulouse 3
• Ecole(s) doctorale(s) : École doctorale Biologie Santé Biotechnologies (Toulouse)

Mots clés

Mots clés contrôlés

Épigénétique

Maladies neurologiques

Bornavirus

Mots clés libres

Bornavirus

Epigénétique

Acétylation des histones

Neurone

Résumé

Analyser les modalités de l'interaction des virus neurotropes avec leurs cellules cibles représente un défi majeur, cela pourrait favoriser notre compréhension de la physiopathologie de certains troubles neurologiques dont l'origine virale est parfois suspectée. Le Bornavirus (BDV), un virus neurotrope, représente un modèle idéal pour analyser les mécanismes moléculaires de la persistance virale dans les neurones et en étudier les conséquences sur l'homéostasie neuronale. Au cours de ma thèse, nous avons découvert une nouvelle forme d'interaction virus/cellule dans laquelle une protéine du BDV perturbe la signalisation épigénétique associée à l'acétylation des histones. Cette perturbation de l'acétylation des histones cellulaires est accompagnée d'une modulation de la réplication virale qui permettrait de favoriser la persistance du BDV dans les neurones tout en limitant les dommages cellulaires associés, démontrant ainsi la parfaite adaptation du BDV à sa cellule hôte.

In response to various environmental stimuli, neurons undertake specific cognitive functions, such as learning and memory. Many studies have shown that epigenetics, notably histone acetylation, is crucial for the regulation of gene expression involved in these processes. Moreover, dysregulation of signaling pathways that regulate epigenetics is clearly recognized as a main actor in the pathogenesis of several neurological disorders. Even if the origin of these disorders is sometimes genetic, their etiology remains elusive and environmental factors are also suspected. In particular, infectious agents are considered as serious candidates, notably for viruses that persist in the central nervous system (CNS). The Bornavirus (BDV) constitutes an interesting model to assess the impact of viral infection on neuronal epigenetics. This non-cytolytic RNA virus infects neurons of the CNS and causes various cognitive disorders in animals. It has the remarkable property to replicate in the nucleus, in close association with chromatin, thus leading to our working hypothesis that it may modify the epigenetics of infected neurons. During my Ph.D., we used primary cultures of cortical neurons to demonstrate that BDV infection decreases H2B and H4 acetylation levels on selected lysine residues, through inhibition of histone acetyltransferase (HAT) activities. We also showed that the viral phosphoprotein was responsible for this perturbation, acting on histone acetylation and HAT activities in a protein kinase C dependent manner. Finally, using pharmacological agents, we observed that histone acetylation levels were correlated with replication of BDV. Thus, BDV action on histone acetylation pathway may represent an original mechanism to control viral replication, thereby favoring long-term persistence in neurons. I am currently examining the consequences of this virus-mediated perturbation on H2B/H4 acetylation at the genome scale, using ChIP-sequencing experiments.