Abstract
Borna disease virus (BDV) is a neurotropic virus that produces neuropsychiatric dysfunction in a wide range of warm-blooded species. Several studies have associated BDV with human psychiatric illness, but the findings remain controversial. Although oligodendrocytes are a major glial component of brain white matter and play a pivotal role in neuronal cell function, BDV's effects on human oligodendrocytes have not been clarified. Here, the effects of two BDV strains, Hu-H1 (isolated from a bipolar patient) and Strain V (a laboratory strain), on the proliferation and apoptosis of human oligodendrocytes were investigated. Three experimental cell lines were constructed: Hu-H1-infected oligodendroglioma (Hu-H1) cells, Strain V-infected oligodendroglioma (Strain V) cells, and non-infected oligodendroglioma (control) cells. BDV infection was assayed by BDV nucleoprotein (p40) immunofluorescence, cell proliferation was assayed by Cell Counting Kit-8 (CCK8), and cell cycle phases and apoptosis were assayed by flow cytometry. Expressions of the apoptosis-related proteins Bax and Bcl-2 were measured by Western blotting. p40 expression was confirmed in Hu-H1 and Strain V on and after day three post-infection. Strain V cells showed significantly greater cellular proliferation than Hu-H1 cells on and after day three post-infection. In Hu-H1 cells, Bax and Bcl-2 expression were significantly increased and decreased, respectively, on and after day three post-infection. In contrast, in Strain V cells, Bax and Bcl-2 expression were significantly decreased and increased, respectively, on and after day three post-infection. In conclusion, Hu-H1 inhibits cellular proliferation and promotes apoptosis in human oligodendrocytes via Bax upregulation and Bcl-2 downregulation. In contrast, Strain V promotes cellular proliferation and inhibits apoptosis in human oligodendrocytes via Bax downregulation and Bcl-2 upregulation. The effects of the Hu-H1 strain (isolated from a bipolar patient) are opposite from those of Strain V (a laboratory strain), thereby providing a proof of authenticity for both.
Highlights
These authors contributed to this work. It is well-known that many DNA viruses interact with the cell cycle machinery, as they are dependent on DNA synthetic enzymes for viral replication
With the notable exceptions of human immunodeficiency virus (HIV) and respiratory syncytial virus (RSV), little is known about the interference of RNA viruses with cell cycle checkpoints and cell apoptosis [1,2,3]
Borna disease virus (BDV)-infected rats show persistent infection accompanied by neurodevelopmental abnormalities that may be attributed to virusinduced neuronal loss or functional neuronal impairment, glial dysfunction, and/or modulation of the developmental fate of neural stem/progenitor cells (NSPCs) [8,9,10]
Summary
It is well-known that many DNA viruses interact with the cell cycle machinery, as they are dependent on DNA synthetic enzymes for viral replication. BDV infection in neonatal rats (producing neonatal Borna disease [NBD]) does generate a persistent CNS infection with a range of neurodevelopmetal abnormalities and complex behavioral changes similar to those observed in autism, schizophrenia, and mood disorders (e.g., anxiety, abnormal playing behavior, deficits in spatial memory and learning). These behavioral and cognitive alterations may be attributed to virus induced neuronal loss or functional neuronal impairment, glial dysfunction, and/or modulation of the developmental fate of neural stem/progenitor cells (NSPCs) [8,9,10]
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