Activation of Microglia by Borna Disease Virus Infection: In Vitro Study

Abstract

Neonatal Borna disease virus (BDV) infection of the rat brain is associated with microglial activation and damage to the certain neuronal populations. Since persistent BDV infection of neurons in vitro is noncytolytic and noncytopathic, activated microglia have been suggested to be responsible for neuronal cell death in vivo. However, the mechanisms of activation of microglia in neonatally BDV-infected rat brain have not been investigated. To address these issues, activation of primary rat microglial cells was studied following exposure to purified BDV or to persistently BDV-infected primary cortical neurons or after BDV infection of primary mixed neuron-glial cultures. Neither purified virus nor BDV-infected neurons alone activated primary microglia as assessed by the changes in cell shape or production of the proinflammatory cytokines. In contrast, in the BDV-infected primary mixed cultures, we observed proliferation of microglia cells that acquired the round morphology and expressed major histocompatibility complex molecules of classes I and II. These manifestations of microglia activation were observed in the absence of direct BDV infection of microglia or overt neuronal toxicity. In addition, compared to uninfected mixed cultures, activation of microglia in BDV-infected mixed cultures was associated with a significantly greater lipopolysaccharide-induced release of tumor necrosis factor alpha, interleukin 1␤, and interleukin 10. Taken together, the present data are the first in vitro evidence that persistent BDV infection of neurons and astrocytes rather than direct exposure to the virus or dying neurons is critical for activating microglia.Borna disease virus (BDV) is a nonsegmented, negativestrand RNA virus that persistently infects the central nervous system (CNS) and causes behavioral abnormalities in a broad spectrum of warm-blooded animals (3,12,22). In neonatally infected rats, BDV causes a life-long persistent infection of the CNS with minimal signs of classical inflammatory cell infiltration (e.g., encephalitis and meningitis) and the absence of overt clinical disease. Nonetheless, neonatal BDV infection is associated with a progressive loss of granule cells in the dentate gyrus of the hippocampus, Purkinje cells in the cerebellum, and GABA-ergic neurons in the neocortex (5,16,18,45).Because BDV establishes a persistent noncytolytic infection in various cell lines and primary neurons and astrocytes in vitro (6,20,34), the mechanisms of neuronal degeneration in vivo remain unclear. Previous studies have indicated that even if the virus does not infect microglia in vivo, neonatal BDV infection is associated with strong microgliosis (6, 22, 38). Intriguingly, BDV-associated microgliosis has been found predominantly in areas of significant neuronal loss, i.e., cortex, hippocampus, and cerebellum (22,33,38,44), leading to the hypothesis that microglia activation plays a central role in BDV-associated neuronal damage (38,44).Microglia, the resident macrophage population in the brain, play a central role ...

Borna Disease Virus Infects Human Neural Progenitor Cells and Impairs Neurogenesis

“…The selective loss of neurons in experimentally infected newborn rats has been puzzling, since BDV has been repeatedly shown to be noncytolytic in differentiated neurons in cultures (16,31). Our findings support the hypothesis that BDV-induced neurodegeneration is due to BDV interference with neurogenesis.…”

“…Our results led us to conclude that the presence of the virus during neuronal differentiation induces neuronal death by interfering with signaling pathways which are important for the proper maturation of neurons. Importantly, the effect of BDV on neurons is restricted to developmental stages, since it has been repeatedly shown in previous works that fully differentiated neurons in cultures were not affected by BDV infection (16,31). The BDV impairment of neurogenesis was already suggested in a study by Friedl et al (12), who used an elegant ex vivo model of organotypic hippocampal slice cultures from newborn rat pups.…”

“…We cannot, however, exclude that other mechanisms also contribute to BDV-induced neuropathogenesis in vivo. The observation of activated microglia in areas of intense neurodegeneration (42), preceding neuronal apoptosis (31), suggested that microgliosis could trigger the demise of infected neurons. Although this hypothesis was not supported by an in vitro study in which the BDV infection of a coculture of differentiated neurons, astrocytes, and microglia led to microglial activation without neurotoxicity (30), it is plausible that microglia exacerbates dysfunction initiated by direct virus infection in the in vivo setting.…”

Downregulation of an Astrocyte-Derived Inflammatory Protein, S100B, Reduces Vascular Inflammatory Responses in Brains Persistently Infected with Borna Disease Virus

“…In either mechanism, the brains with downregulated S100B expression might succumb to the stressful environment and cause the apoptosis of neural cells. Previous studies have demonstrated that in BDV-infected neonatal rat brains, reactivation of glial cells may be associated with specific neuronal cell apoptosis rather than viral tropism and virusspecific immune responses (29,50). These studies support our hypothesis that sustained activation of astrocytes in the persistently infected brains may exhaust the glial functions concerned with cellular survival.…”

Glial activation involvement in neuronal death by Japanese encephalitis virus infection

“…The CNS response to ischaemia, degenerative diseases and viral infection is largely manifested by neuronal loss and inflammatory responses (Gao et al, 2002;Liao et al, 2002;Chen et al, 2004;Raung et al, 2005;German et al, 2006;Ovanesov et al, 2006;Ghoshal et al, 2007;van Marle et al, 2007;Saxena et al, 2008;Swarup et al, 2008). Generally, the onset and/or interactive crosstalk of neuronal injury and neuroinflammation play a critical role in the pathogenesis of neurological disorders.…”