Persistent Borna Disease Virus Infection Confers Instability of HSP70 mRNA in Glial Cells during Heat Stress

Abstract

Borna disease virus (BDV) is a highly neurotropic RNA virus that causes neurological disorders in many vertebrate species. Although BDV readily establishes lasting persistence, persistently infected cells maintain an apparently normal cell phenotype in terms of morphology, viability, and proliferation. In this study, to understand the regulation of stress responses in BDV infection, we investigated the expression of heat shock proteins (HSPs) in glial cells persistently infected with BDV. Interestingly, we found that BDV persistence did not upregulate HSP70 expression even in cells treated with heat stress. Furthermore, BDV-infected glial cells exhibited rapid rounding and detachment from the culture plate under various stressful conditions. Immunofluorescence analysis demonstrated that heat stress rapidly disrupts the cell cytoskeleton only in persistently infected cells, suggesting a lack of thermotolerance. Intriguingly, we found that although persistently infected glial cells expressed HSP70 mRNA after heat stress, its expression rapidly disappeared during the recovery period. These observations indicated that persistent BDV infection may affect the stability of HSP70 mRNA. Finally, we found that the double-stranded RNA-dependent protein kinase (PKR) is expressed at a constant level in persistently infected cells with or without heat shock. Considering the interrelationship between HSP70 and PKR production, our data suggest that BDV infection disturbs the cellular stress responses to abolish antiviral activities and maintain persistence.Borna disease virus (BDV) is a neurotropic virus that belongs to the Mononegavirales order. Natural BDV infections have been found in a wide variety of vertebrates, suggesting that the host range of this virus probably includes all warmblooded animals (17,22). BDV infects the central nervous system (CNS) of many animal species and causes behavioral disturbances reminiscent of autism, schizophrenia, and mood disorders (17,38,41,50). Thus, studies on this virus provide an important paradigm for the mechanisms by which viral infection induces neurobehavioral disorders.

Borna Disease Virus Infects Human Neural Progenitor Cells and Impairs Neurogenesis

“…However, although HNPCs are highly permissive to the virus, they did not appear to be particularly vulnerable. As has been observed in other cell types, including primary cultures of neurons and astrocytes from rats (16,44) and other cell lines, BDV infection proceeds without an overt pathogenic effect in HNPCs, impairing neither their survival nor their undifferentiated phenotype. Therefore, our results argue against a specific vulnerability of immature neural cells to BDV infection.…”

Susceptibility of human and rat neural cell lines to infection by SARS-coronavirus

“…Infection with SARS-CoV. In addition to Vero E6, the following cell lines were examined for infection by SARS-CoV: human oligodendroglioma-derived cell line OL [22] which was generated at the Wistar Institute, Philadelphia, USA [23]; rat glioma-derived cell line C6 [24]; human intestine-derived cell line CaCo-2; canine kidney-derived cell line MDCK; rabbit kidney-derived cell line RK13. All these cells were similarly infected with SARS-CoV at a multiplicity of infection (MOI) of 10.…”

Characterization of a Borna disease virus field isolate which shows efficient viral propagation and transmissibility

“…Primary cortical neurons were isolated from Lewis rats (SLC, Shizuoka, Japan), as previous described [12].…”