Antiviral Type I Interferon Pathway Activity Increases with Human Neuronal Differentiation, Promoting Enhanced Defense against Neurotropic Arboviruses.

Type I Interferon;Neural Progenitor Cell;Innate Immune;Neuronal Maturation;Human Embryonic Stem Cell;Arbovirus;Microbiology and Immunology;Science;Microbiology and Immunology

Farmer, JocelynLaouar, Yasmina ;

University of Michigan

关键词: Type I Interferon;    Neural Progenitor Cell;    Innate Immune;    Neuronal Maturation;    Human Embryonic Stem Cell;    Arbovirus;    Microbiology and Immunology;    Science;    Microbiology and Immunology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/98040/jrfarmer_2.pdf?sequence=2&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Neurotropic arboviruses are leading causative agents of viral encephalitis worldwide.These pathogens specifically infect neurons to cause acute encephalitic disease and permanent neurological sequelae in humans, which are particularly severe in the pediatric population.Pathogenesis of neurotropic arboviruses correlates with the degree of neuronal maturity in the host, and populations of neural stem/progenitor cells demonstrate particular susceptibility to viral infection.However, the mechanism(s) by which defense against a neurotropic arbovirus increases with human neuronal development have yet to be fully dissected.To investigate changes in neuronal innate immune function over the course of development, we established a model for the in vitro derivation of enriched populations of human neural progenitor cells (NPCs) and mature human neurons from human embryonic stem cells (hESCs).Using the hESC model in conjunction with primary cortical rat neurons and human neuronal cells, we identified novel maturation-dependent changes in the neuronal type I interferon (IFN) signaling pathway, including upregulation of the IFN-α/β receptor 2 subunit (IFNAR2) on the cell surface of mature neurons.Furthermore, we determined that basal upregulation of IFNAR2 is sufficient for increased type I IFN-dependent inhibition of neurotropic arbovirus replication.Finally, we dissected a downstream mechanism by which type I IFN mediates its antiviral activity by identifying MxA as a functional inhibitor of neurotropic arbovirus replication in human neuronal cells.Together our data demonstrate that the innate antiviral immune function of a human neuron increases with differentiation, resulting in enhanced defense against neurotropic arbovirus infection.Our careful dissection of maturation-dependent changes in the neuronal type I IFN signaling pathway in vitro paves the way for future investigations, which will determine the impact of neuron-specific innate immune function on global host defense against neurotropic arboviruses in vivo.