The interferon beta (IFNB) response is a main cellular actor of the innate antiviral response necessary to stop viral replication and propagation. A fine-tuning of the IFNB response is required in order to rapidly stop viral replication and propagation while limiting its negative side effects, especially in the brain where de-regulated IFNB expression has been associated to cognitive disorders and neurodegenerative diseases.
In continuity with our previous work on host-viral interactions and the regulation of IFNB gene expression (Bamia, 2021; Marcato, 2016; Josse, 2012; Mansuroglu, 2010; Le May, 2008), we are presently working on the role of the IFNB response on microglia activation, neuron/microglia crosstalk and Tau pathology in the context of viral infection. Specially in the case of Zika virus (ZIKV), a neurotropic Flavivirus for which there is now evidence in humans, macaquesand mice that delayed neuropathies of the central nervous system (CNS), associated with cognitive disorders, can develop following neonatal and adult ZIKV infections. Yet, how mature neurons respond to ZIKV remains mostly unexplored.
While working in vitro, with primary cultures of neurons and microglia (separately and combined) and in vivo, following intracranial ZIKV inoculation of young adult immunocompetent mice we have demonstrated that ZIKV infection induces a delayed neuronal IFNB expression and response specifically impairing the capacity of neurons to stop viral replication (Manet, 2022 under submission). The accumulation of ZIKV RNA on infected neurons appeared correlated to the pathological phosphorylation of Tau (pTau) protein, a major constituent of neurons whose abnormal phosphorylation and aggregation is associated with neurodegeneration and for which we have established a role in maintaining the integrity of the neuronal genome (Mokrani-Benhelli, 2018; Mansuroglu, 2016; Sultann, 2011). We also observed the presence of pTau in vivo, in the brain of ZIKV-infected mice where clusters of pTau-labeled neurons were surrounded by reactive non-infected microglial cells.
Microglia are the phagocytic cells of the brain that play a role in immunosurveillance, neuroprotection and shaping neuronal circuits. Alteration of microglia activation in response to infection can lead to abnormal phagocytosis of functional synapses and subsequent cognitive disorders. Presently, our results indicate a major role for IFNB in activating microglial cells in the context of vial infections.
Our work is carried out in close collaboration with Xavier Montagutelli (Mouse Genetics laboratory, Institut Pasteur) and Marie-Christine Galas (Alzheimer & Tauopathies laboratory, UMRS1172). It is financed by CNRS, INSERM, Université Paris Cité, European Joint Program Neurodegenerative Disease (JPND) project INSTALZ (03/2016-03/2019 coordinated by M-C.Galas) and an ongoing ANR NeuroZika grant (10/2020-10/2024 coordinated by E.Bonnefoy).
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