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

Fares, M. et al. (2020) Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection. Journal of Neuroinflammation, 17, 76. (doi: 10.1186/s12974-020-01756-x) (PMID:32127025)

[img]
Preview
Text
212292.pdf - Published Version
Available under License Creative Commons Attribution.

6MB

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.

Item Type:Articles
Additional Information:This study was financially supported by the French National Institute for Agriculture, Food and the Environment (INRAE) and DIM MalInf (Ile de France). MF was financially supported by a Ph.D. fellowship from INRA and the Paris Institute of Technology for Life, Food, and Environmental Sciences (AgroParisTech). GG was financially supported by Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases grant ANR-10-LABX-62-IBEID.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Fares, Dr Mazigh
Creator Roles:
Fares, M.Conceptualization, Methodology, Formal analysis, Writing – original draft
Authors: Fares, M., Cochet-Bernoin, M., Gonzalez, G., Montero-Menei, C. N., Blanchet, O., Benchoua, A., Boissart, C., Lecollinet, S., Richardson, J., Haddad, N., and Coulpier, M.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:Journal of Neuroinflammation
Publisher:BMC
ISSN:1742-2094
ISSN (Online):1742-2094
Copyright Holders:Copyright © 2020 The Authors
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record