Pathogenesis of viral infections of the developing and adult central nervous system
Coordinators: D. Dunia / C. Malnou
AXIS 1 : Viral interference with neuronal homeostasis
AXIS 2 : Role of extracellular placental vesicles during congenital viral infections
AXIS 3 : Impact of pathogens on neuronal epigenetics and behavior
To date, the mechanisms whereby pathogens can interfere with brain function are not well understood and the determinants responsible for the associated diseases are poorly defined. Our team has a strong interest in studying the mechanisms and consequences of pathogen infection of the central nervous system (CNS), from the developing to the adult brain.
For our different projects, we use several paradigms of CNS infections: infection by Borna Disease virus (BoDV), congenital infection by human Cytomegalovirus (hCMV) and Zika virus (ZIKV) and persistence of the parasite Toxoplasma gondii in the adult CNS.
In the context of the adult brain, we assess the pathophysiological and behavioral outcome of pathogen persistence in the CNS, either due to the pathogen itself or to the accompanying neuroinflammation. We also aim at identifying processes which could be highjacked by neurotropic pathogens and contribute to neuronal impairment or the resulting neurodegenerative processes.
In the case of congenital infections during pregnancy, we study how viruses can disrupt the normal neurodevelopmental program and lead to severe sequelae in the newborn. In this setting, we examine the modalities of congenital infection and the resulting impact on neonatal brain development. These later aspects are facilitated by the integration in our team of several clinicians from the neonatology unit in Toulouse hospital, who help us to facilitate the clinical translation of our findings.
AXIS 1: Viral interference with neuronal homeostasis
In our laboratory, we study neuronal infection by Borna disease virus (BoDV-1), because we believe that this virus provides an ideal paradigm for studying the behavioral correlates of CNS viral infections. BoDV-1 is the perfect example of a neurotropic virus which achieves long-term persistence, while causing minimal damage to neurons. BoDV-1 infection, however, leads to brain dysfunction and disease, as a result of the selective interference with signaling pathways that are crucial for proper central nervous system (CNS) homeostasis. The ongoing project of our team are:
- BoDV-1 as a neuroprotective tool? We recently showed that the BoDV-1 X protein, or a cell-permeable peptide derived from the X protein were able to prevent neurodegeneration in different in vitro and in vivo settings, by acting at the mitochondrial level.
We are now pursuing different aims : first, to gain further insight on the mechanisms underlying the neuroprotective properties of X, by deciphering its mitochondrial interactome and impact on mitochondrial physiology and dynamics; next, to further document the proof of concept of using X-derived peptides for neuroprotection, by testing its therapeutic potential in various models of chronic neurodegeneration, in the frame in collaborations in Toulouse, Bordeaux or Paris with experts in various neurodegenerative diseases.
- Structure-function analysis of the BoDV replication machinery and impact on neuronal epigenetics. Considering the recent identification of BoDV-1 as a potential zoonotic agent, we have established collaborations with structural biologists and virus-host interaction experts. Our goals are to perform a comprehensive analysis of the BoDV replication machinery, a large-scale mapping of virus/host polypeptide interplays and of its consequences on viral fitness and on neuronal physiology. Together with Dr. E. Suberbielle in our team, we notably analyze the resulting consequences on neuronal epigenetics.
- Development of a novel nanoelectronics platform to probe neuronal activity. In collaboration with physicists from the LAAS-CNRS laboratory in Toulouse, we have developed nanowire-based devices (Nano-electrode arrays, or NEA) interfaced with living neurons. We are now testing the relevance of such NEA to measure different parameters of neuronal activity (response to stimulation, plasticity, etc..) upon infection, expression of proteins of interest (BoDV-1 P and X proteins, notably), as well as after exposure to other neuronal insults, such as amyloid ß peptide or proinflammatory cytokines. This project is supported by the CNRS MITI (Mission for Transversal and Interdisciplinary Initiatives)
Head : D. Dunia
AXIS 2: Role of extracellular placental vesicles during congenital viral infections
Our research project explores the emerging concept that infection of the placenta with viruses such as human cytomegalovirus (hCMV) or Zika virus (ZIKV) could alter the amount and / or composition of placental extracellular vesicles (EVs) (Figure 1), which could then promote the dissemination of the virus towards the fetus and contribute to the alteration in brain development observed during congenital infections.
- Impact of the infection of placental cells on the secretion and composition of EVs and consequences for the development of the fetal central nervous system.
Our results indicate that, upon infection with hCMV, there is a phenotypic modification of exosomes secreted from placental histocultures of early placentas or cultured trophoblast lines. The phenotypic characteristics of EVs isolated from infected cells suggest that they could act in a paracrine manner to facilitate the infection of surrounding or distant cells and that they thus participate in the pathophysiology of the disorders observed during pregnancy and in the fetus. Our work also suggests that EVs could play a role of biomarkers during infection in order to evaluate, via a simple blood test from the mother during pregnancy, the state of the placenta.
- Role of the miRNA C19MC cluster carried by placental EVs.
EVs derived from the placenta are capable of conferring antiviral protection on target cells, via the action of the cluster of miRNA C19MC, contained in the EVs. Thanks to an original model of cells deleted for the entire cluster, we are studying the modalities of the antiviral action of these miRNAs. In addition, we are investigating whether placental EVs can also protect human neural stem cells from viral infection. Finally, we are evaluating their expression profile in EVs circulating in pregnant women during infections by hCMV, ZIKV or SARS-CoV2 in order to assess whether these infections modify their expression profile within EVs during pregnancy.
In conclusion, we hope to provide new pathophysiological elements to better understand the etiology of congenital viral infections, in order to improve the diagnosis and also offer new perspectives for therapeutic intervention.
Head : C. Malnou
AXIS 3: Impact of pathogens on neuronal epigenetics and behavior
The hypothesis at the center of our research interests:
Because of their lifelong persistence in the brain or the immune responses raised against them, pathogens in the central nervous system could contribute to neuronal dysfunction, cognitive senescence and neuropsychiatric diseases. From a mechanistic point of view, neuronal epigenetics, which is key to cognitive plasticity, may play a fundamental role in these disorders. In particular, we have shown that DNA double-strand breaks (DSB) represent a critical mode of regulation of neuronal epigenetics. We are interested in deciphering the mechanisms whereby DSB affect neuronal function and in understanding how perturbations in sensing, production and/or repair of DSB may underlie the behavioral impairment that is observed in many inflammatory, infectious, or age-related diseases affecting the CNS.
3 lines of research are currently being pursued:
- Role of DSB in the pathophysiology of infection by Borna disease virus (BoDV).
Our recent data indicate that DSB contribute to the regulation of BoDV replication with consequences on the activity of the infected neuronal networks. Understanding how this structurally simple virus disrupts the DSB response will allow us to elucidate the mechanisms of DSB response in neurons.
- Infection of the central nervous system by Toxoplasma gondii, a common human parasite.
Studying the impact of various strains of this parasite on behavior and the underlying mechanisms serves as a model for deciphering how a persistent infection in the brain could contribute to cognitive and immune senescence during healthy vs. pathological aging. In collaboration with Team 6 (link).
- Epigenetic dysregulations of neuronal function in response to chronic inflammation. Due to aging or a lifelong response to environmental threats, chronic inflammation and in particular, the systemic increases in inflammatory mediators, are thought to have long-lasting impact on behavior. We study the how DSB response and epigenetic changes may be fundamental mechanisms underlying chronic inflammation-induced behavioral deficits.
Finally, the results of our research will allow us to elucidate the key mechanisms of DNA DSB response in neurons under pathophysiological circumstances, to maintain the physiological balance between DNA DSB generation and repair. In the long-term, our research may pave the way for new therapies against chronic neuroinflammation or Alzheimer’s disease.
Head : Suberbielle Elsa
Borna disease virus docks on neuronal DNA double-strand breaks to replicate and dampens neuronal activity Journal Article
Human cytomegalovirus infection is associated with increased expression of the lissencephaly gene PAFAH1B1 encoding LIS1 in neural stem cells and congenitally infected brains Journal Article
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Hspa9/Mortalin mediates axo-protection and modulates mitochondrial dynamics in neurons Journal Article
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Fatal encephalitis and Borna Disease Virus-1 seropositivity in two kidney-transplant patients living in the same non-endemic area Journal Article
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Genetic and pharmacological inactivation of astroglial connexin 43 differentially influences the acute response of antidepressant and anxiolytic drugs. Journal Article
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Imprinted microRNA gene clusters in the evolution, development, and functions of mammalian placenta Journal Article
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MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2 Journal Article
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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.
- Karine Bourgade
- Marion Szelechowski
- Alexandre Bétourné
- Amine Benarbia
- Carine Duval
- Valérie Duplan
- Céline Monnet
- Jeffrey Bajramovic
- Florent Marty
- Luca Bettamin
- Maude Rolland
- Cécile Ferré
- Leila Khajavi
- Maïlys Mouysset
- Joao Proença
- Emilie Bonnaud
- Caroline Charlier
- Grégoire Chevalier
- Christine Prat
- Elsa Suberbielle
- Romain Volmer
- Aymeric Hans
- Aline Taveira
- Marine Fraisse
- Charlotte Foret
Within the Center
- Jacques Izopet/Bernard Lagane
- Jérôme Ausseil/Rémy Poupot
- Nicolas Blanchard
- Sylvie Guerder/Nicolas Fazilleau
- Roland Liblau/Abdel Saoudi
- Team MINDING, Centre de recherche sur la cognition animale (CRCA), CNRS UMR 5169, Toulouse (P. Belenguer, M-C. Miquel).
- Laboratoire d’analyse et d’architecture des systèmes, LAAS-CNRS, Toulouse (G. Larrieu).
- 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).
- Team METAMAL, CRCT, Toulouse (J.E. Sarry)
- Institut des cellules souches pour le traitement et l’étude des maladies monogéniques, Unité UMR861-ISTEM, Evry (M. Peschanski, A.Benchoua).
- IPBS, Toulouse (O. Schiltz)
- Institut Curie, CNRS UMR144, Paris (G. Raposo et G. D’Angelo).
- MCD, CBI, Toulouse (J. Cavaillé).
- IBS, Genoble (T. Crépin).
- PRISM, Lille (E. Coyaud).
- Inserm UMR 1058, Montpellier (Y. Simonin).
- CHU Toulouse, services gynéco-obstétrique et néonatologie.
- Kyoto University, Japan (Pr. K. Tomonaga)
- The Gorgas Memorial Institute for Health and Diseases, Panama city, Panama (S Lopez-Verges)
- The Gladstones Institute, USCF, USA (Pr L. Mucke)