Team 07 – D. Dunia / C. Malnou - Institut Toulousain des Maladies Infectieuses et Inflammatoires

Pathogenesis of viral infections of the developing and adult central nervous system

Coordinators: D. Dunia / C. Casper

Scientific Objectives

Our team investigates the mechanisms and consequences of viral infections of the adult and developing central nervous system. Using several DNA and RNA viruses (notably Bornavirus, Zika virus and Cytomegalovirus), we study in particular: the impact of viral persistence on neuronal activity and plasticity, as well as on neuronal epigenetics; the impact of infections on neuronogenesis and neuronal differentiation, using a model of human neural stem cells (NSCs); the gene profiling or analysis of the secretion of soluble factors by infected NSCs or primary neuronal cultures; the modalities of congenital infection by the placental route, in collaboration with the neonatology department of Purpan university hospital.

Our Projects

AXIS 1: Viral interference with neuronal homeostasis

As obligatory parasites, viruses have evolved strategies to persist efficiently in their hosts. In the case of the central nervous system, viruses often achieve persistence while causing minimal damage to neurons, which have only limited capacities of renewal. Viral persistence, however, can cause brain dysfunction and cause disease, as a result of the selective interference with signaling pathways that are crucial for proper central nervous system (CNS) homeostasis.In our laboratory, we study the model of Borna disease virus (BDV) because it which provides an ideal paradigm for studying the behavioral correlates of CNS viral infections. The current projects of our team deal with:

Illustration-theme-Dunia

1. The analysis of the impairment of neuronal plasticity due to BDV infection. We showed that it results from interference with Protein Kinase C (PKC)-dependent signaling and that the BDV phosphoprotein (P) is the viral determinant mediating this interference, by serving as a PKC kinase decoy substrate when expressed in neurons. Moreover, our recent data show that isolated expression of P in the brain also impairs neuronal function and behavior.

2. The analysis of the potential of the BDV X protein and of X-derived peptides, to protect against neurodegeneration, even outside of the viral context. Control of cellular apoptosis is indeed a strategy often used by viruses to limit cellular damage. We showed that the BDV X protein has a clear neuroprotective effect in vitro, by acting at the mitochondrial level and by altering mitochondrial dynamics. This protection has also been observed in vivo in a mouse model of Parkinson’s disease. We are now exploring the possibility to use the X protein (or X-derived peptides) as novel treatments for neurodegenerative diseases. In parallel, we are studying the mechanisms of protection conferred by the X protein, notably its impact on mitochondrial physiology and dynamics.

3. The development of new methods for the detection of neuronal activity at the single-cell level, in collaboration with physicists from the LAAS-CNRS laboratory (Toulouse). We use nanowire (NW)-based devices to interface nanoelectronic devices with living neurons to address the impact of pharmacological agents and virus-derived proteins on neuronal activity.

Head : D. Dunia

AXIS 2: Impact of pathogens on neuronal epigenetics

We are interested in the study of neuronal epigenetics and its deregulation during infection. Different projects are developed:

1. Interaction of Bornavirus (BDV) with histone acetylation in neurons and its consequences for behavior. Recent work from our team indicates that BDV alters histone acetylation in neurons due to the interference of a viral protein, the phosphoprotein, with cellular histone acetyl transferase activities. We are now exploring the consequence of this epigenetic dysregulation for neuronal function at genomic, transcriptomic and behavioral level, notably by developing transgenic mouse models, which will be used for ChIP-seq, RNAseq and behavioral studies.

2. Regulation of MeCP2 stability and chromatin dynamics by its phosphorylation. MeCP2, which mutations are responsible for the neurodevelopmental Rett syndrome, is a chromatin-interacting protein, highly abundant in neurons, implicated in the regulation of gene expression. We are interested in the study of two unexplored MeCP2 parameters: its stability and its dynamic interaction with chromatin in live cells, and the impact on its phosphorylation on these parameters.

3. DNA double-strand breaks response as a novel epigenetic process in neurons: roles and mechanisms in cognition, aging and neuroinflammatory diseases. Epigenetic alterations impact neuronal function, as they cause durable changes of the chromatin structure that affect gene expression. In this context, DNA double-strand breaks (DSBs) are emerging as central regulators of neuronal epigenetics. We are interested in deciphering the mechanisms whereby DSBs affect neuronal function and in understanding how perturbations in sensing, production and/or repair of DSBs may underlie the behavioral impairment that is observed in many inflammatory, infectious, or age-related diseases affecting the CNS.

Heads : C. Malnou – E. Suberbielle

AXIS 3: Congenital viral infections and impact on the developing brain

Congenital infection by human cytomegalovirus (HCMV) is the leading cause of brain lesions (hearing loss, mental retardation, microcephalia…) in newborns (0.1% of all births).

We investigate the outcomes of HCMV infection on human neural stem cells (NSC). We have shown that HCMV infection triggers the activity of the transcription factor PPAR gamma (PPARg), which impairs in vitro neuronogenesis. Our results have been validated by the immunohistological examination of brain samples from infected fetus. We now characterize the target genes for PPARg upon NSC infection by HCMV, including a gene known to be critical for brain development. We also investigate the outcomes of placental infection by HCMV on NSC homeostasis, using an original disease model based on ex vivo infected human placental explants combined with NSCs.
Our work aims at a better knowledge of the pathogenesis of HCMV infection, both in the placenta and central nervous system.
In addition, our know-how enables us to investigate the outcomes of other congenital infections, such as Zika virus and its impact on brain development.

Heads : S. Chavanas – C. Casper

Other information

Members

Publications

2018

Betourne, A; Szelechowski, M; Thouard, A; Abrial, E; Jean, A; Zaidi, F; Foret, C; Bonnaud, E M; Charlier, C M; Suberbielle, E; Malnou, C E; Granon, S; Rampon, C; Gonzalez-Dunia, D

Hippocampal expression of a virus-derived protein impairs memory in mice Journal Article

Proc Natl Acad Sci U S A, 115 (7), pp. 1611-1616, 2018, ISSN: 1091-6490 (Electronic) 0027-8424 (Linking).

Pathogenesis of viral infections of the developing and adult central nervous system

Scientific Objectives

Our Projects

AXIS 1: Viral interference with neuronal homeostasis

Head : D. Dunia

AXIS 2: Impact of pathogens on neuronal epigenetics

We are interested in the study of neuronal epigenetics and its deregulation during infection. Different projects are developed:

AXIS 3: Congenital viral infections and impact on the developing brain

Congenital infection by human cytomegalovirus (HCMV) is the leading cause of brain lesions (hearing loss, mental retardation, microcephalia…) in newborns (0.1% of all births).

Other information

Members

Publications

2018

2017

2016

2015

2014

2013

2011

2010

2009

Societal impact

Alumni

Collaborations

France Parkinson

AFM

Association Française du Syndrome de Rett

Union Nationale des Aveugles et Déficients Visuels

CNRS

Université Toulouse Paul Sabatier

Région Occitanie

GSK

Agence nationale de la recherche

INSERM

France Alzheimer

Marie Curie actions

NARSAD