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1. Comparison of intra- and inter-host genetic diversity in rabies virus during experimental cross-species transmission.

Author

Emilie M Bonnaud, Cécile Troupin, Laurent Dacheux, Edward C Holmes, Elodie Monchatre-Leroy, Marion Tanguy, Christiane Bouchier, Florence Cliquet, Jacques Barrat, and Hervé Bourhy

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

The development of high-throughput genome sequencing enables accurate measurements of levels of sub-consensus intra-host virus genetic diversity and analysis of the role played by natural selection during cross-species transmission. We analysed the natural and experimental evolution of rabies virus (RABV), an important example of a virus that is able to make multiple host jumps. In particular, we (i) analyzed RABV evolution during experimental host switching with the goal of identifying possible genetic markers of host adaptation, (ii) compared the mutational changes observed during passage with those observed in natura, and (iii) determined whether the colonization of new hosts or tissues requires adaptive evolution in the virus. To address these aims, animal infection models (dog and fox) and primary cell culture models (embryo brain cells of dog and fox) were developed and viral variation was studied in detail through deep genome sequencing. Our analysis revealed a strong unidirectional host evolutionary effect, as dog-adapted rabies virus was able to replicate in fox and fox cells relatively easily, while dogs or neuronal dog cells were not easily susceptible to fox adapted-RABV. This suggests that dog RABV may be able to adapt to some hosts more easily than other host variants, or that when RABV switched from dogs to red foxes it lost its ability to adapt easily to other species. Although no difference in patterns of mutation variation between different host organs was observed, mutations were common following both in vitro and in vivo passage. However, only a small number of these mutations also appeared in natura, suggesting that adaptation during successful cross-species virus transmission is a complex, multifactorial evolutionary process.

Published
2019
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2. Hippocampal expression of a virus-derived protein impairs memory in mice

Author

Alexandre Betourne, Charlotte Foret, Caroline M. Charlier, Claire Rampon, Cécile E. Malnou, E. Abrial, Elsa Suberbielle, Emilie M. Bonnaud, Sylvie Granon, Anne Thouard, Daniel Gonzalez-Dunia, Arnaud Jean, Marion Szelechowski, Falek Zaidi, Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut cellule souche et cerveau (U846 Inserm - UCBL1), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroplasticité des comportements de reproduction = Neuroplasticity of Reproductive Behaviors (NPS-11), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut des sciences du cerveau de Toulouse. (ISCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Laboratoire de génétique et biologie cellulaire (LGBC), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (SBRI), Université Claude Bernard Lyon 1 (UCBL), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Paris-Saclay (Neuro-PSI), Dunia, Daniel, Centre de Recherches sur la Cognition Animale - UMR5169 (CRCA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Cell signaling, Memory, Long-Term, [SDV]Life Sciences [q-bio], Hippocampus, Hippocampal formation, Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Animals, Protein phosphorylation, Phosphorylation, Borna disease virus, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Protein Kinase C, Protein kinase C, Neurons, Viral Structural Proteins, Neuronal Plasticity, Multidisciplinary, [SCCO.NEUR]Cognitive science/Neuroscience, Dentate gyrus, Biological Sciences, Phosphoproteins, 3. Good health, Cell biology, 030104 developmental biology, Borna Disease, Dentate Gyrus, Mutation, Synaptic plasticity, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cognition Disorders, 030217 neurology & neurosurgery
Abstract

International audience; The analysis of the biology of neurotropic viruses, notably of their interference with cellular signaling, provides a useful tool to get further insight into the role of specific pathways in the control of behavioral functions. Here, we exploited the natural property of a viral protein identified as a major effector of behavioral disorders during infection. We used the phosphoprotein (P) of Borna disease virus, which acts as a decoy substrate for protein kinase C (PKC) when expressed in neurons and disrupts synaptic plasticity. By a lentiviral-based strategy, we directed the singled-out expression of P in the dentate gyrus of the hippocampus and we examined its impact on mouse behavior. Mice expressing the P protein displayed increased anxiety and impaired long-term memory in contextual and spatial memory tasks. Interestingly, these effects were dependent on P protein phosphorylation by PKC, as expression of a mutant form of P devoid of its PKC phosphorylation sites had no effect on these behaviors. We also revealed features of behavioral impairment induced by P protein expression but that were independent of its phosphorylation by PKC. Altogether, our findings provide insight into the behavioral correlates of viral infection , as well as into the impact of virus-mediated alterations of the PKC pathway on behavioral functions. dentate gyrus | hippocampus | virus | memory | protein kinase C

Published
2018
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3. Lyssavirus matrix protein cooperates with phosphoprotein to modulate the Jak-Stat pathway

Author

Florian Sonthonnax, Emilie M. Bonnaud, Hervé Bourhy, David Merino, Benoit Besson, Grégory Jouvion, Florence Larrous, Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris], Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris]-Université de Paris (UP), This research was supported by the European Union Seventh Framework Programme (FP7/2007-2017) PREDEMICS grant #278433, European Project: 278433,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,PREDEMICS(2011), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, Cytoplasm, Mice, 0302 clinical medicine, Interferon, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], STAT1, Promoter Regions, Genetic, Mice, Inbred BALB C, Multidisciplinary, Virulence, biology, Viral immune evasion, Chemistry, NF-kappa B, JAK-STAT signaling pathway, 3. Good health, Cell biology, STAT1 Transcription Factor, Interferon Type I, Medicine, Signal transduction, Signal Transduction, medicine.drug, Myeloma protein, Science, Virus-host interactions, Article, Viral Matrix Proteins, Viral Proteins, 03 medical and health sciences, Th2 Cells, medicine, Animals, Humans, Viral matrix protein, Janus Kinase 1, Phosphoproteins, Immunity, Innate, 030104 developmental biology, Phosphoprotein, Mutagenesis, Site-Directed, biology.protein, Lyssavirus, 030217 neurology & neurosurgery, Viral pathogenesis, HeLa Cells
Abstract

Phosphoprotein (P) and matrix protein (M) cooperate to undermine the immune response to rabies virus (RABV) infections. While P is involved in the modulation of the Jak-Stat pathway through the cytoplasmic retention of interferon (IFN)-activated STAT1 (pSTAT1), M interacts with the RelAp43-p105-ABIN2-TPL2 complex, to efficiently inhibit the nuclear factor-κB (NF-κB) pathway. Using transfections, protein-complementation assays, reverse genetics and DNA ChIP, we identified a role of M protein in the control of Jak-Stat signaling pathway, in synergy with the P protein. In unstimulated cells, both M and P proteins were found to interact with JAK1. Upon type-I IFN stimulation, the M switches toward pSTAT1 interaction, which results in an enhanced capacity of P protein to interact with pSTAT1 and restrain it in the cytoplasm. Furthermore, the role for M-protein positions 77, 100, 104 and 110 was also demonstrated in interaction with both JAK1 and pY-STAT1, and confirmed in vivo. Together, these data indicate that M protein cooperates with P protein to restrain in parallel, and sequentially, NF-κB and Jak-Stat pathways.

Published
2019
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4. Comparison of intra- and inter-host genetic diversity in rabies virus during experimental cross-species transmission

Author

Marion Tanguy, Jacques Barrat, Emilie M. Bonnaud, Florence Cliquet, Elodie Monchatre-Leroy, Laurent Dacheux, Edward C. Holmes, Hervé Bourhy, Cécile Troupin, Christiane Bouchier, Centre collaborateur de l'OMS - Rage / World Health Organization Collaboration Centres - Rabies (CC-OMS / WHO-CC), Institut Pasteur [Paris] (IP)-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), The University of Sydney, Laboratoire de la rage et de la faune sauvage de Nancy (LRFSN), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Génomique (Plate-Forme) - Genomics Platform, Institut Pasteur [Paris] (IP), This work was supported by European Union Seventh Framework Programme PREDEMICS (grant number 278433) and by the Agence Nationale de la Recherche (grant number BSV3-0019). The Genomics Platform is member of ªFrance Génomiqueº consortium (ANR10-INBS- 09-08). HB, LD and EB were supported by the European Virus Archive goes Global (EVAg) project that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 653316. ECH is funded by an ARC Australian Laureate Fellowship (FL170100022)., We are grateful to Karine Reynaud from the Unit Biology of Development and Reproduction of the Ecole Nationale Vétérinaire d'Alfort for providing the dog embryos, and to Benoît Combe of the Entente de Lutte Interdépartementale contre les Zoonoses of Malzeville for his help in obtaining fox embryos. We also thank Laurence Ma and Magali Tichit from the Genomics Platform for technical assistance with NGS sequencing., ANR-12-BSV3-0019,Viva&host,Variabilité génétique au sein des populations de virus à ARN négatif non segmenté et adaptation à l'hôte(2012), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), European Project: 278433,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,PREDEMICS(2011), European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), Institut Pasteur [Paris]-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), and Institut Pasteur [Paris]

Subjects
Male, RNA viruses, Evolutionary Genetics, Cross-species transmission, Foxes, medicine.disease_cause, Pathology and Laboratory Medicine, Salivary Glands, MESH: Dogs, Medicine and Health Sciences, MESH: Animals, Dog Diseases, Biology (General), MESH: High-Throughput Nucleotide Sequencing, MESH: Evolution, Molecular, Genetics, Mammals, 0303 health sciences, Experimental evolution, Mutation, 030302 biochemistry & molecular biology, Microbial Genetics, High-Throughput Nucleotide Sequencing, Eukaryota, 3. Good health, MESH: Rabies virus, Medical Microbiology, Viral evolution, Viral Pathogens, Vertebrates, Viruses, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Host adaptation, Pathogens, Anatomy, Research Article, Evolutionary Processes, MESH: Mutation, QH301-705.5, Rabies, MESH: Dog Diseases, Immunology, Biology, Microbiology, MESH: Host-Parasite Interactions, Virus, Viral Evolution, Cell Line, Host-Parasite Interactions, Evolution, Molecular, 03 medical and health sciences, Rabies Virus, Dogs, Exocrine Glands, MESH: Rabies, Evolutionary Adaptation, Virology, medicine, Animals, Molecular Biology, Microbial Pathogens, 030304 developmental biology, Evolutionary Biology, MESH: Foxes, Host (biology), Rabies virus, Organisms, Biology and Life Sciences, RC581-607, Organismal Evolution, MESH: Male, MESH: Cell Line, Amniotes, Microbial Evolution, Parasitology, Lyssavirus, Immunologic diseases. Allergy, Digestive System, MESH: Female
Abstract

The development of high-throughput genome sequencing enables accurate measurements of levels of sub-consensus intra-host virus genetic diversity and analysis of the role played by natural selection during cross-species transmission. We analysed the natural and experimental evolution of rabies virus (RABV), an important example of a virus that is able to make multiple host jumps. In particular, we (i) analyzed RABV evolution during experimental host switching with the goal of identifying possible genetic markers of host adaptation, (ii) compared the mutational changes observed during passage with those observed in natura, and (iii) determined whether the colonization of new hosts or tissues requires adaptive evolution in the virus. To address these aims, animal infection models (dog and fox) and primary cell culture models (embryo brain cells of dog and fox) were developed and viral variation was studied in detail through deep genome sequencing. Our analysis revealed a strong unidirectional host evolutionary effect, as dog-adapted rabies virus was able to replicate in fox and fox cells relatively easily, while dogs or neuronal dog cells were not easily susceptible to fox adapted-RABV. This suggests that dog RABV may be able to adapt to some hosts more easily than other host variants, or that when RABV switched from dogs to red foxes it lost its ability to adapt easily to other species. Although no difference in patterns of mutation variation between different host organs was observed, mutations were common following both in vitro and in vivo passage. However, only a small number of these mutations also appeared in natura, suggesting that adaptation during successful cross-species virus transmission is a complex, multifactorial evolutionary process., Author summary Understanding the mechanisms that underpin the cross-species transmission and host adaptation of rabies virus (RABV) remains an important part of the ongoing goal to reduce and eliminate rabies. We utilized next-generation sequencing to perform a deep comparative analysis of the genomic evolution of RABV subpopulations during host adaptation in culture and in animals, with the aim of determining the molecular mechanisms involved in the host-species or tissue adaptation of rabies virus. In particular, we aimed to determine whether experimental evolution can recapitulate evolution in nature. Our results suggest that a limited number of mutations that appeared following both in vitro and in vivo passage were observed in natura. This study also suggests that dog RABV may be able to adapt to some hosts more easily than other host variants.

Published
2019
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5. Histone acetylation in neuronal (dys)function

Author

Emilie M. Bonnaud, Cécile E. Malnou, and Elsa Suberbielle

Subjects
0301 basic medicine, cognition, QH301-705.5, Environment, General Biochemistry, Genetics and Molecular Biology, histone acetyltransferase, Epigenesis, Genetic, Histones, 03 medical and health sciences, Cellular and Molecular Neuroscience, Memory, Animals, Humans, Genetic Predisposition to Disease, Epigenetics, Biology (General), Epigenesis, Neurons, Regulation of gene expression, Neuronal Plasticity, synaptic plasticity, biology, epigenetics, histone acetylation, Acetylation, Neurodegenerative Diseases, General Medicine, Histone acetyltransferase, neuron, 030104 developmental biology, Histone, Gene Expression Regulation, Mutation, Synaptic plasticity, histone deacetylase, biology.protein, Histone deacetylase, Neuroscience
Abstract

Cognitive functions require the expression of an appropriate pattern of genes in response to environmental stimuli. Over the last years, many studies have accumulated knowledge towards the understanding of molecular mechanisms that regulate neuronal gene expression. Epigenetic modifications have been shown to play an important role in numerous neuronal functions, from synaptic plasticity to learning and memory. In particular, histone acetylation is a central player in these processes. In this review, we present the molecular mechanisms of histone acetylation and summarize the data underlying the relevance of histone acetylation in cognitive functions in normal and pathological conditions. In the last part, we discuss the different mechanisms underlying the dysregulation of histone acetylation associated with neurological disorders, with a particular focus on environmental causes (stress, drugs, or infectious agents) that are linked to impaired histone acetylation.

Published
2016

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

Author

Cécile E. Malnou, Emilie M. Bonnaud, Alexandre Betourne, Anne Thouard, Marion Szelechowski, Daniel Gonzalez-Dunia, Charlotte Foret, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
viruses, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Immunology, Virus Replication, Microbiology, Virus, Epigenesis, Genetic, Histones, Rats, Sprague-Dawley, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, Animals, Epigenetics, Borna disease virus, Cells, Cultured, Neurons, Viral Structural Proteins, biology, Acetylation, Histone acetyltransferase, Phosphoproteins, 3. Good health, Chromatin, Virus-Cell Interactions, Histone, Viral replication, Insect Science, Phosphoprotein, Host-Pathogen Interactions, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, Protein Processing, Post-Translational
Abstract

Understanding 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. IMPORTANCE Persistent 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.

Published
2015
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7. HIV-1 reprograms the migration of macrophages

Author

Oliver T. Fackler, Serge Benichou, Christel Vérollet, Paul Jolicoeur, Isabelle Fourquaux, Cassandre Kinnaer, Renaud Poincloux, Emilie M. Bonnaud, Andrea Imle, Brigitte Raynaud-Messina, Isabelle Maridonneau-Parini, and Shanti Souriant

Subjects
Genetically modified mouse, Podosome, Immunology, Cell, Motility, HIV Infections, Mice, Transgenic, Biochemistry, Cell Membrane Structures, Mice, Cell Movement, Cell Line, Tumor, medicine, Macrophage, Animals, Humans, nef Gene Products, Human Immunodeficiency Virus, Cells, Cultured, Kinase, business.industry, Macrophages, Mesenchymal stem cell, Cell Biology, Hematology, Cellular Reprogramming, Cell biology, medicine.anatomical_structure, Host-Pathogen Interactions, HIV-1, Proto-Oncogene Proteins c-hck, Signal transduction, business, Wiskott-Aldrich Syndrome Protein
Abstract

Macrophages are motile leukocytes, targeted by HIV-1, thought to play a critical role in host dissemination of the virus. However, whether infection impacts their migration capacity remains unknown. We show that 2-dimensional migration and the 3-dimensional (3D) amoeboid migration mode of HIV-1-infected human monocyte-derived macrophages were inhibited, whereas the 3D mesenchymal migration was enhanced. The viral protein Nef was necessary and sufficient for all HIV-1-mediated effects on migration. In Nef transgenic mice, tissue infiltration of macrophages was increased in a tumor model and in several tissues at steady state, suggesting a dominant role for mesenchymal migration in vivo. The mesenchymal motility involves matrix proteolysis and podosomes, cell structures constitutive of monocyte-derived cells. Focusing on the mechanisms used by HIV-1 Nef to control the mesenchymal migration, we show that the stability, size, and proteolytic function of podosomes are increased via the phagocyte-specific kinase Hck and Wiskott-Aldrich syndrome protein (WASP), 2 major regulators of podosomes. In conclusion, HIV-1 reprograms macrophage migration, which likely explains macrophage accumulation in several patient tissues, which is a key step for virus spreading and pathogenesis. Moreover, Nef points out podosomes and the Hck/WASP signaling pathway as good candidates to control tissue infiltration of macrophages, a detrimental phenomenon in several diseases.

Published
2014

8. HIV-1 Nef alters podosomes and promotes the mesenchymal migration in human macrophages

Author

Emilie M. Bonnaud, Annabelle Corjeon, Isabelle Maridonneau-Parini, Christel Vérollet, Cassandre Kinnaer, and Renaud Poincloux

Subjects
Podosome, medicine.diagnostic_test, Chemistry, Proteolysis, Mesenchymal stem cell, virus diseases, Bioinformatics, Cell biology, Extracellular matrix, Infectious Diseases, Virology, Poster Presentation, medicine, Macrophage, Tyrosine kinase, Function (biology), Proto-oncogene tyrosine-protein kinase Src
Abstract

Results Here, we examined the migration ability of HIV-1infected primary human macrophages. We show that HIV-1 infection modifies dramatically the migration of macrophages in 3-dimentionnal (3D) environments. While the amoeboid migration mode is inhibited upon infection, another migration mode specifically used by macrophages in dense 3D environments, the mesenchymal migration mode, is greatly enhanced. HIV-1 negative factor (Nef) is responsible for both effects on macrophage migration modes. Consistently with an increase in mesenchymal migration capacities, Nef accumulates around F-actin structures necessary for proteolysis of the extracellular matrix, e.g. podosomes, and alters their structure, function and dynamics. Mechanistically, HIV-1-induced podosome modifications and mesenchymal macrophage migration depend on Nef’s ability to activate the macrophage-specific Src tyrosine kinase, Hck.

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