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1. Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection

Author

Mazigh Fares, Marielle Cochet-Bernoin, Gaëlle Gonzalez, Claudia N. Montero-Menei, Odile Blanchet, Alexandra Benchoua, Claire Boissart, Sylvie Lecollinet, Jennifer Richardson, Nadia Haddad, and Muriel Coulpier

Subjects
Neurotropic virus, Flavivirus, Tick-borne encephalitis virus, Central nervous system, Human neuronal/glial cells, Viral tropism, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Tick-borne encephalitis virus (TBEV) is a member of the Flaviviridae family, Flavivirus genus, which includes several important human pathogens. It is responsible for neurological symptoms that may cause permanent disability or death, and, from a medical point of view, is the major arbovirus in Central/Northern Europe and North-Eastern Asia. TBEV tropism is critical for neuropathogenesis, yet little is known about the molecular mechanisms that govern the susceptibility of human brain cells to the virus. In this study, we sought to establish and characterize a new in vitro model of TBEV infection in the human brain and to decipher cell type-specific innate immunity and its relation to TBEV tropism and neuropathogenesis. Method Human neuronal/glial cells were differentiated from neural progenitor cells and infected with the TBEV-Hypr strain. Kinetics of infection, cellular tropism, and cellular responses, including innate immune responses, were characterized by measuring viral genome and viral titer, performing immunofluorescence, enumerating the different cellular types, and determining their rate of infection and by performing PCR array and qRT-PCR. The specific response of neurons and astrocytes was analyzed using the same approaches after enrichment of the neuronal/glial cultures for each cellular subtype. Results We showed that infection of human neuronal/glial cells mimicked three major hallmarks of TBEV infection in the human brain, namely, preferential neuronal tropism, neuronal death, and astrogliosis. We further showed that these cells conserved their capacity to mount an antiviral response against TBEV. TBEV-infected neuronal/glial cells, therefore, represented a highly relevant pathological model. By enriching the cultures for either neurons or astrocytes, we further demonstrated qualitative and quantitative differential innate immune responses in the two cell types that correlated with their particular susceptibility to TBEV. Conclusion Our results thus reveal that cell type-specific innate immunity is likely to contribute to shaping TBEV tropism for human brain cells. They describe a new in vitro model for in-depth study of TBEV-induced neuropathogenesis and improve our understanding of the mechanisms by which neurotropic viruses target and damage human brain cells.

Published
2020
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2. A plasmid DNA-launched SARS-CoV-2 reverse genetics system and coronavirus toolkit for COVID-19 research.

Author

Suzannah J Rihn, Andres Merits, Siddharth Bakshi, Matthew L Turnbull, Arthur Wickenhagen, Akira J T Alexander, Carla Baillie, Benjamin Brennan, Fiona Brown, Kirstyn Brunker, Steven R Bryden, Kerry A Burness, Stephen Carmichael, Sarah J Cole, Vanessa M Cowton, Paul Davies, Chris Davis, Giuditta De Lorenzo, Claire L Donald, Mark Dorward, James I Dunlop, Matthew Elliott, Mazigh Fares, Ana da Silva Filipe, Joseph R Freitas, Wilhelm Furnon, Rommel J Gestuveo, Anna Geyer, Daniel Giesel, Daniel M Goldfarb, Nicola Goodman, Rory Gunson, C James Hastie, Vanessa Herder, Joseph Hughes, Clare Johnson, Natasha Johnson, Alain Kohl, Karen Kerr, Hannah Leech, Laura Sandra Lello, Kathy Li, Gauthier Lieber, Xiang Liu, Rajendra Lingala, Colin Loney, Daniel Mair, Marion J McElwee, Steven McFarlane, Jenna Nichols, Kyriaki Nomikou, Anne Orr, Richard J Orton, Massimo Palmarini, Yasmin A Parr, Rute Maria Pinto, Samantha Raggett, Elaine Reid, David L Robertson, Jamie Royle, Natalia Cameron-Ruiz, James G Shepherd, Katherine Smollett, Douglas G Stewart, Meredith Stewart, Elena Sugrue, Agnieszka M Szemiel, Aislynn Taggart, Emma C Thomson, Lily Tong, Leah S Torrie, Rachel Toth, Margus Varjak, Sainan Wang, Stuart G Wilkinson, Paul G Wyatt, Eva Zusinaite, Dario R Alessi, Arvind H Patel, Ali Zaid, Sam J Wilson, and Suresh Mahalingam

Subjects
Biology (General), QH301-705.5
Abstract

The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/, constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science.

Published
2021
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3. Transcriptomic Studies Suggest a Coincident Role for Apoptosis and Pyroptosis but Not for Autophagic Neuronal Death in TBEV-Infected Human Neuronal/Glial Cells

Author

Mazigh Fares, Kamila Gorna, Noémie Berry, Marielle Cochet-Bernoin, François Piumi, Odile Blanchet, Nadia Haddad, Jennifer Richardson, and Muriel Coulpier

Subjects
central nervous system, flavivirus, neuronal death, pathological modeling, tick-borne encephalitis virus, TNF family members, Microbiology, QR1-502
Abstract

Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, Flavivirus genus, is responsible for neurological symptoms that may cause permanent disability or death. With an incidence on the rise, it is the major arbovirus affecting humans in Central/Northern Europe and North-Eastern Asia. Neuronal death is a critical feature of TBEV infection, yet little is known about the type of death and the molecular mechanisms involved. In this study, we used a recently established pathological model of TBEV infection based on human neuronal/glial cells differentiated from fetal neural progenitors and transcriptomic approaches to tackle this question. We confirmed the occurrence of apoptotic death in these cultures and further showed that genes involved in pyroptotic death were up-regulated, suggesting that this type of death also occurs in TBEV-infected human brain cells. On the contrary, no up-regulation of major autophagic genes was found. Furthermore, we demonstrated an up-regulation of a cluster of genes belonging to the extrinsic apoptotic pathway and revealed the cellular types expressing them. Our results suggest that neuronal death occurs by multiple mechanisms in TBEV-infected human neuronal/glial cells, thus providing a first insight into the molecular pathways that may be involved in neuronal death when the human brain is infected by TBEV.

Published
2021
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4. Virus-host interactions during tick-borne bunyavirus infection

Author

Benjamin Brennan and Mazigh Fares

Subjects
Virology
Abstract

The Bunyavirales order is the largest grouping of RNA viruses, comprising emerging and re-emerging human, plant and animal pathogens. Bunyaviruses have a global distribution and many members of the order are transmitted by arthropods. They have evolved a plethora of mechanisms to manipulate the regulatory processes of the infected cell to facilitate their own replicative cycle, in hosts of disparate phylogenies. Interest in virus-vector interactions is growing rapidly. However, current understanding of tick-borne bunyavirus cellular interaction is heavily biased to studies conducted in mammalian systems. In this short review, we summarise current understandings of how tick-borne bunyaviruses utilise major cellular pathways (innate immunity, apoptosis and RNAi responses) in mammalian or tick cells to facilitate virus replication.

Published
2022

5. Transcriptomic studies suggest a coincident role for apoptosis and pyroptosis but not for autophagic neuronal death in TBEV-infected human neuronal/glial cells

Author

Nadia Haddad, Jennifer Richardson, Odile Blanchet, Mazigh Fares, François Piumi, Kamila Gorna, Marielle Cochet-Bernoin, Muriel Coulpier, Noémie Berry, Virologie UMR1161 (VIRO), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MRC - University of Glasgow Centre for Virus Research, Centre de Ressources Biologiques [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), PRES Université Nantes Angers Le Mans (UNAM), Biologie moléculaire et immunologie parasitaires et fongiques (BIPAR), École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), INRAE, DIM MalInf, École nationale vétérinaire d'Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and École nationale vétérinaire d'Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé

Subjects
tick-borne encephalitis virus, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Central nervous system, Apoptosis, Biology, Microbiology, Encephalitis Viruses, Tick-Borne, TNF-Related Apoptosis-Inducing Ligand, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, flavivirus, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, Pyroptosis, medicine, Humans, Progenitor cell, TNF family members, 030304 developmental biology, Neurons, MESH: Encephalitis Viruses, Tick-Borne, 0303 health sciences, Communication, Autophagy, regulated cell death, Human brain, biology.organism_classification, central nervous system, neuronal death, QR1-502, 3. Good health, Cell biology, Receptors, TNF-Related Apoptosis-Inducing Ligand, Flavivirus, Infectious Diseases, medicine.anatomical_structure, Astrocytes, pathological modeling, Neuroglia, 030217 neurology & neurosurgery
Abstract

International audience; Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, Flavivirus genus, is responsible for neurological symptoms that may cause permanent disability or death. With an incidence on the rise, it is the major arbovirus affecting humans in Central/Northern Europe and North-Eastern Asia. Neuronal death is a critical feature of TBEV infection, yet little is known about the type of death and the molecular mechanisms involved. In this study, we used a recently established pathological model of TBEV infection based on human neuronal/glial cells differentiated from fetal neural progenitors and transcriptomic approaches to tackle this question. We confirmed the occurrence of apoptotic death in these cultures and further showed that genes involved in pyroptotic death were up-regulated, suggesting that this type of death also occurs in TBEV-infected human brain cells. On the contrary, no up-regulation of major autophagic genes was found. Furthermore, we demonstrated an up-regulation of a cluster of genes belonging to the extrinsic apoptotic pathway and revealed the cellular types expressing them. Our results suggest that neuronal death occurs by multiple mechanisms in TBEV-infected human neuronal/glial cells, thus providing a first insight into the molecular pathways that may be involved in neuronal death when the human brain is infected by TBEV.

Published
2021

6. A plasmid DNA-launched SARS-CoV-2 reverse genetics system and coronavirus toolkit for COVID-19 research

Author

Natalia Cameron-Ruiz, Siddharth Bakshi, Mark Dorward, Agnieszka M. Szemiel, Wilhelm Furnon, Matthew Elliott, Kathy Li, Rory Gunson, Giuditta De Lorenzo, Kirstyn Brunker, James G Shepherd, Anne Orr, Laura Sandra Lello, Dario R. Alessi, Stuart G. Wilkinson, Aislynn Taggart, Fiona Brown, Leah S. Torrie, C. James Hastie, Paul G. Wyatt, Margus Varjak, Joseph Hughes, Jamie Royle, Rajendra Lingala, Jenna Nichols, Daniel Mair, Xiang Liu, David Robertson, Vanessa M. Cowton, Chris Davis, Colin Loney, Kyriaki Nomikou, Nicola Goodman, James I. Dunlop, Sarah Cole, Natasha Johnson, Sam J. Wilson, Steven McFarlane, Kerry A. Burness, Claire L. Donald, Clare Johnson, Alain Kohl, Mazigh Fares, Rommel J. Gestuveo, Elaine Reid, Douglas G. Stewart, Paul Davies, Marion McElwee, E. Thomson, Akira J T Alexander, Daniel M. Goldfarb, Ali Zaid, Carla Baillie, Hannah Leech, Arthur Wickenhagen, Arvind H. Patel, Sainan Wang, Samantha Raggett, Gauthier Lieber, Benjamin Brennan, Katherine Smollett, Rute Maria Pinto, Vanessa Herder, Rachel Toth, Lily Tong, Joseph R Freitas, Eva Zusinaite, Suresh Mahalingam, Suzannah J. Rihn, Ana da Silva Filipe, Massimo Palmarini, Anna Geyer, Daniel M. Giesel, Steven R. Bryden, Andreas Merits, Richard J. Orton, Stephen Carmichael, Meredith Stewart, Elena Sugrue, Matthew L. Turnbull, Yasmin A Parr, and Karen Kerr

Subjects
0301 basic medicine, RNA viruses, Viral Diseases, Pulmonology, Coronaviruses, Physiology, viruses, medicine.disease_cause, Biochemistry, Mice, 0302 clinical medicine, Plasmid, Medical Conditions, Immune Physiology, Pandemic, Chlorocebus aethiops, Biology (General), skin and connective tissue diseases, Pathology and laboratory medicine, Coronavirus, Immune System Proteins, General Neuroscience, Serine Endopeptidases, Methods and Resources, virus diseases, Medical microbiology, 3. Good health, Precipitation Techniques, Infectious Diseases, Viruses, Angiotensin-Converting Enzyme 2, Antibody, SARS CoV 2, Pathogens, General Agricultural and Biological Sciences, Plasmids, COVID-19 Vaccines, SARS coronavirus, Viral protein, QH301-705.5, Morpholines, Immunology, Biology, Research and Analysis Methods, Microbiology, General Biochemistry, Genetics and Molecular Biology, Antibodies, 03 medical and health sciences, Respiratory Disorders, Open Reading Frames, Viral Proteins, medicine, Immunoprecipitation, Animals, Humans, Codon, Vero Cells, Medicine and health sciences, SARS, General Immunology and Microbiology, Biology and life sciences, SARS-CoV-2, fungi, Organisms, Viral pathogens, Hydrazones, Proteins, COVID-19, Covid 19, Virology, Reverse genetics, Reverse Genetics, Microbial pathogens, body regions, Open reading frame, 030104 developmental biology, Pyrimidines, A549 Cells, Respiratory Infections, Vero cell, biology.protein, 030217 neurology & neurosurgery
Abstract

The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/, constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science., To help meet the ensuing demand for COVID-19 reagents, this article presents an openly available ‘coronavirus toolkit’ (https://mrcppu-covid.bio) and describes the generation and validation of these tools, including a simple SARS-CoV-2 reverse genetics system and a near-comprehensive panel of SARS-CoV-2 antibodies.

Published
2021

7. Additional file 4 of Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection

Author

Mazigh Fares, Cochet-Bernoin, Marielle, GaëLle Gonzalez, Montero-Menei, Claudia, Blanchet, Odile, Benchoua, Alexandra, Boissart, Claire, Lecollinet, Sylvie, Richardson, Jennifer, Haddad, Nadia, and Coulpier, Muriel

Abstract

Additional file 4. Antiviral response in enriched neurons, astrocytes and unsorted cells (PCR array data, 24 hpi).

Published
2020
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8. Additional file 3 of Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection

Author

Mazigh Fares, Cochet-Bernoin, Marielle, GaëLle Gonzalez, Montero-Menei, Claudia, Blanchet, Odile, Benchoua, Alexandra, Boissart, Claire, Lecollinet, Sylvie, Richardson, Jennifer, Haddad, Nadia, and Coulpier, Muriel

Subjects
nervous system
Abstract

Additional file 3. TBEV-induced antiviral response in neuronal/glial cells (PCR array data, 24 hpi).

Published
2020
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9. Additional file 1 of Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection

Author

Mazigh Fares, Cochet-Bernoin, Marielle, GaëLle Gonzalez, Montero-Menei, Claudia, Blanchet, Odile, Benchoua, Alexandra, Boissart, Claire, Lecollinet, Sylvie, Richardson, Jennifer, Haddad, Nadia, and Coulpier, Muriel

Abstract

Additional file 1. Primer pairs used for qRT-PCR analyses.

Published
2020
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10. Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection

Author

Muriel Coulpier, Claudia N. Montero-Menei, Mazigh Fares, Marielle Cochet-Bernoin, Jennifer Richardson, Nadia Haddad, Sylvie Lecollinet, Claire Boissart, Gaelle Gonzalez, Alexandra Benchoua, Odile Blanchet, MRC - University of Glasgow Centre for Virus Research, Virologie UMR1161 (VIRO), École nationale vétérinaire d'Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre de Ressources Biologiques [CHU d'Angers] (CRB CHU d'Angers BB-0033-00038), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Biologie moléculaire et immunologie parasitaires et fongiques (BIPAR), École nationale vétérinaire d'Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), French National Institute for Agriculture, Food and the Environment (INRAE) DIM MalInf (Ile de France) Paris Institute of Technology for Life, Food, and Environmental Sciences (AgroParisTech), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Bernardo, Elizabeth, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA), and École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé

Subjects
Cell type, Human neuronal/glial cells, Cell Culture Techniques, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC346-429, Encephalitis Viruses, Tick-Borne, Neurotropic virus, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Viral tropism, lcsh:Neurology. Diseases of the nervous system, Cells, Cultured, Tropism, 030304 developmental biology, Neurons, Innate immunity, 0303 health sciences, Innate immune system, biology, Research, Flavivirus, Human brain, biology.organism_classification, medicine.disease, Immunity, Innate, Neural stem cell, 3. Good health, Astrogliosis, Viral Tropism, medicine.anatomical_structure, Central nervous system, Astrocytes, Neuropathogenesis, Pathological modeling, Tick-borne encephalitis virus, Disease Susceptibility, Neuroscience, Encephalitis, Tick-Borne, 030217 neurology & neurosurgery
Abstract

Tick-borne encephalitis virus (TBEV) is a member of theFlaviviridaefamily,Flavivirusgenus, which includes several important human pathogens. It is responsible for neurological symptoms that may cause permanent disability or death, and, from a medical point of view, is the major arbovirus in Central/Northern Europe and North-eastern Asia. TBEV tropism is critical for neuropathogenesis, yet, little is known about the molecular mechanisms that govern the susceptibility of human brain cells to the virus. In this study, we sought to establish and characterize a newin vitromodel of TBEV infection in the human brain and to decipher cell type-specific innate immunity and its relation to TBEV tropism and neuropathogenesis. We showed that infection of neuronal/glial cultures derived from human fetal neural progenitor cells (hNPCs) mimicked three major hallmarks of TBEV infection in the human brain, namely, preferential neuronal tropism, neuronal death and astrogliosis. We also showed that these cells had conserved their capacity to build an antiviral response against TBEV. TBEV-infected neuronal/glial cells, therefore, represented a highly relevant pathological model. By enriching the cultures in either human neurons or astrocytes, we further demonstrated qualitative and quantitative differential innate immune responses in the two cell types that correlated with their particular susceptibility to TBEV. Our results thus reveal that cell type-specific innate immunity is likely to contribute to shaping TBEV tropism for human brain cells. They offer a newin vitromodel to further study TBEV-induced neuropathogenesis and improve our understanding of the mechanisms by which neurotropic viruses target and damage human brain cells.Author summaryTick-borne encephalitis virus (TBEV), a neurotropicFlavivirusthat is responsible for encephalitis in humans, is of growing concern in Europe. Indeed, over the last two decades the number of reported cases has continuously increased and the virus has spread into new geographical areas. Whereas it is well established that neurons are the main target of TBEV in the human brain, the mechanisms that underlie this preferential tropism have not yet been elucidated. Here, we used neuronal/glial cells derived from human fetal neural progenitors to establish and characterize a newin vitropathological model that mimics major hallmarks of TBEV infectionin vivo; namely, neuronal tropism, neuronal death and astrogliosis. Using this highly relevant model, we showed that human neurons and astrocytes were both capable of developing an innate immune response against TBEV, but with dissimilar magnitudes that correlated with differential susceptibility to TBEV. Our results thus revealed that TBEV tropism for subsets of human brain cells is likely to depend on cell-type specific innate immunity. This improves our understanding of the mechanisms by which neurotropic viruses target and damage human brain cells and may help guide development of future therapies.

Published
2019

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