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Pathological modeling of tick-borne encephalitis virus infection and induced antiviral response in neurons and astrocytes using human neural progenitor-derived cells.

Abstract : Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, genus Flavivirus, is, from a medical point of view, the most important arbovirus in Europe and North-East Asia. It is responsible for febrile illness and, in some cases, for neurological manifestations ranging from mild meningitis to severe encephalomyelitis that can be fatal. Despite its medical importance, TBEV-induced neuropathogenesis remains poorly understood. Here, we used human neural cells differentiated from fetal neural progenitor cells (hNPCs) to model the infection in vitro and to decipher the mechanisms by which the virus damages the human brain. Our results showed that neurons and glial cells, namely astrocytes and oligodendrocytes, were permissive to TBEV. Neurons were massively infected and subjected to a dramatic cytopathic effect (60% loss 7 days post-infection). Astrocytes were also infected, although at lower levels, and the infection had a moderate effect on their survival (30% loss 7 days post infection), inducing a hypertrophied morphology characteristic of astrogliosis. Thus, two major cellular events described in TBEV-infected human brain (i.e. neuronal loss and astrogliosis) were reproduced in this in vitro cellular model, showing its relevance to study TBEV-induced neuropathogenesis. We therefore used it to tackle TBEV induced antiviral response. Using PCR arrays, we first showed that TBEV induced a strong antiviral response characterized by the overexpression of viral sensors, cytokines and interferon-stimulated genes (ISGs). Then, setting up enriched cultures of human neurons and human astrocytes, we further showed that the two cellular types were participating in the global antiviral response. However, astrocytes developed a stronger antiviral response than neurons. These results, by demonstrating that human neurons and human astrocytes have unique antiviral potential, suggest that their particular susceptibility to TBEV infection is due to their different capacity to mount a protective antiviral response.
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Mazigh Fares. Pathological modeling of tick-borne encephalitis virus infection and induced antiviral response in neurons and astrocytes using human neural progenitor-derived cells.. Microbiology and Parasitology. Institut agronomique, vétérinaire et forestier de France, 2018. English. ⟨NNT : 2018IAVF0025⟩. ⟨tel-02949218⟩

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