Pathogenesis of viral infections of the developing and adult central nervous system
Coordinators: D. Dunia / C. Casper
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.
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:
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
Proc Natl Acad Sci U S A, 115 (7), pp. 1611-1616, 2018, ISSN: 1091-6490 (Electronic) 0027-8424 (Linking).
Arthritis Res Ther, 19 (1), pp. 124, 2017, ISSN: 1478-6362 (Electronic) 1478-6354 (Linking).
Histone acetylation in neuronal (dys)function Journal Article
Biomol Concepts, 7 (2), pp. 103-16, 2016, ISSN: 1868-503X (Electronic) 1868-5021 (Linking).
J Gen Virol, 97 (12), pp. 3215-3224, 2016, ISSN: 1465-2099 (Electronic) 0022-1317 (Linking).
Neurogenesis (Austin), 3 (1), pp. e1231654, 2016, ISSN: 2326-2133 (Print) 2326-2133 (Linking).
FASEB J, 30 (4), pp. 1523-33, 2016, ISSN: 1530-6860 (Electronic) 0892-6638 (Linking).
Zika virus in semen and spermatozoa Journal Article
Lancet Infect Dis, 16 (10), pp. 1106-7, 2016, ISSN: 1474-4457 (Electronic) 1473-3099 (Linking).
PLoS Pathog, 12 (4), pp. e1005547, 2016, ISSN: 1553-7374 (Electronic) 1553-7366 (Linking).
Pharm Biol, 54 (11), pp. 2782-2785, 2016, ISSN: 1744-5116 (Electronic) 1388-0209 (Linking).
J Virol, 89 (11), pp. 5996-6008, 2015, ISSN: 1098-5514 (Electronic) 0022-538X (Linking).
J Virol, 89 (2), pp. 1070-82, 2015, ISSN: 1098-5514 (Electronic) 0022-538X (Linking).
Cytomegalovirus Infection Triggers the Secretion of the PPARgamma Agonists 15-Hydroxyeicosatetraenoic Acid (15-HETE) and 13-Hydroxyoctadecadienoic Acid (13-HODE) in Human Cytotrophoblasts and Placental Cultures Journal Article
PLoS One, 10 (7), pp. e0132627, 2015, ISSN: 1932-6203 (Electronic) 1932-6203 (Linking).
J Virol, 89 (13), pp. 6792-804, 2015, ISSN: 1098-5514 (Electronic) 0022-538X (Linking).
PLoS Pathog, 11 (4), pp. e1004859, 2015, ISSN: 1553-7374 (Electronic) 1553-7366 (Linking).
Nat Commun, 6 , pp. 8897, 2015, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).
Nat Commun, 5 , pp. 5181, 2014, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).
Bornavirus and target cells: An almost sincere friendship Journal Article
Virologie, 18 (4), pp. 187-200, 2014.
J Virol, 87 (22), pp. 12339-48, 2013, ISSN: 1098-5514 (Electronic) 0022-538X (Linking).
Neurons as targets for T cells in the nervous system Journal Article
Trends Neurosci, 36 (6), pp. 315-24, 2013, ISSN: 1878-108X (Electronic) 0166-2236 (Linking).
Nat Neurosci, 16 (5), pp. 613-21, 2013, ISSN: 1546-1726 (Electronic) 1097-6256 (Linking).
J Vis Exp, (82), pp. 50833, 2013, ISSN: 1940-087X (Electronic) 1940-087X (Linking).
PLoS Pathog, 7 (11), pp. e1002393, 2011, ISSN: 1553-7374 (Electronic) 1553-7366 (Linking).
Arch Virol, 155 (5), pp. 789-93, 2010, ISSN: 1432-8798 (Electronic) 0304-8608 (Linking).
PLoS Pathog, 5 (5), pp. e1000425, 2009, ISSN: 1553-7374 (Electronic) 1553-7366 (Linking).
Our research aims at a better understanding of the impact of viruses on the developing brain and on neuronal homeostasis and also of the pathophysiology of congenital viral infections. To this aim, we use two viral paradigms: the model system Bornavirus (BDV) and congenital infection by human cytomegalovirus (HCMV), which is a public health issue.
The remarkable features of BDV pathogenesis, notably its predominant tropism for limbic structures in the brain (cortex and hippocampus), constitute a fascinating model of viral interaction with the brain and make it a very valuable tool to gain insight on the pathogenesis of many human neurological diseases. A better understanding of the underlying mechanisms may provide new physiopathological clues for a better understanding of many human neurological diseases of unclear etiology.
The development of these projects is facilitated the gathering in the team of researchers, assistant professors and clinicians with leading and complementary expertise. Moreover, our connection with the neonatal department of the Children’s Hospital of Toulouse and the maternity ward offers opportunities for translational research, from basic to patient-oriented research.
- Marion Szelechowski
Now Post-Doc, CRCA Toulouse, France
- Alexandre Bétourné
Now Chief Medical Officer, Above and Beyond NB Atlanta GA, USA
- Amine Benarbia
Now R&D Manager, NOR-FEED, Beaucouzé, France
- Carine Duval
Now looking for new opportunities
- Valérie Duplan
Now co-head, Flow cytometry and cell sorting platform, CPTP, Toulouse, France
- Céline Monnet
Now Head, Molecular Evolution group, LFB, Lille, France
- Jeffrey Bajramovic
Now researcher, BPRC, Rijswijk, The Netherlands
- Maude Rolland
Master and Ph.D. Student, 2012-2017
Now searching for postdoctoral opportunities
- Cécile Ferré
Master and Ph.D. Student, 2012-2016
Now Student, Medical School, Toulouse, France
- Leila Khajavi
Master Student, 2016-2017
Now Ph.D. Student, CPTP, Toulouse
- Maïlys Mouisset
Master Student, 2016-2017
Now looking for new opportunities
- Joao Proença
Erasmus student, 2015
Now Ph.D. Student, Porto University, Porto, Portugal
- Emilie Bonnaud
Master and Ph.D. Student, 2011-2015
Now Post-Doc, H. Bourhy’s lab, Pasteur Institute, Paris, France
- Caroline Charlier
Master and Ph.D. Student, 2009-2013
Now Science and Technology teacher, France
- Grégoire Chevalier
Ph.D. Student, 2008-2011
Now Scientific Officer – Associate Researcher, Pasteur Institute, Paris, France
- Christine Prat
Ph.D. Student, 2005-2009
Now Business Developer, European Virus Archive project (EVAg), Protisvalor, Marseille, France
- Elsa Suberbielle
Ph.D. Student, 2004-2008
Now Research Associate (CR CNRS), CPTP, Toulouse, France
- Romain Volmer
Master and Ph.D. Student, 2001-2005
Now Assistant Professor, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France
- Aymeric Hans
Master and Ph.D. Student, 1998-2003
Now Team Leader, Laboratory for Equine Pathology, ANSES, Dozulé, France
- Aline Taveira
Master Student, 2008-2009
Now Safety Data Associate, UBC, Geneva, Switzerland
- Marine Fraisse
Now Engineer, CRCT, Toulouse, France
- Charlotte Foret
Now Engineer, INRA-ENVT, Toulouse, France
Within the Center
- N. Blanchard (Team 8)
- G. Martin-Blondel (Team 5)
- J-M. Mansuy, J. Izopet (Team 6)
- Team REMEMBeR, Centre de recherche sur la cognition animale (CRCA), CNRS UMR 5169, Toulouse (C. Florian, B. Guiard, C. Rampon).
- Team MINDING, Centre de recherche sur la cognition animale (CRCA), CNRS UMR 5169, Toulouse (P. Belenguer, M-C. Miquel).
- Unité de Mathématiques et Informatique Appliquées de Toulouse (MIAT), INRA UR875, Auzeville (M. Zittnicki).
- Laboratoire d’analyse et d’architecture des systèmes, LAAS-CNRS, Toulouse (G. Larrieu, L. Nicu).
- Inserm U 862, Neurocentre Magendie, Bordeaux (G. Le Masson).
- Centre de Recherche ICM INSERM/UPMC UMR 975 – CNRS UMR 7225, Paris (S. Hunot).
- Centre de Biologie Paris Seine (IBPS), CNRS UNMR 8256, Paris (J-M. Peyrin).
- Institut des cellules souches pour le traitement et l’étude des maladies monogéniques, Unité UMR861-ISTEM, Evry (M. Peschanski, A.Benchoua).
- Centre national de référence de l’infection congénitale à HCMV, service de virologie de l’hôpital Necker, Paris (M. Leruez-Ville).
- Freiburg University, Germany (Pr. M. Schwemmle)
- University College London, UK (Pr GP Schiavo, S. Debaisieux)
- The Gorgas Memorial Institute for Health and Diseases, Panama city, Panama (S Lopez-Verges).
- University of Victoria, Victoria, Canada (Pr. J. Ausio)
- The Gladstones Institute, USCF, USA (Pr L. Mucke)
- WuHan Institute of Virology, Wuhan, China (Pr MH Luo)
- Neurotec Department, Karolinska Institute, Stockholm, Sweden (Pr C Sodeberg-Naucler)