Persistent Borna Disease Virus (BDV) infection activates microglia prior to a detectable loss of granule cells in the hippocampus

Neonatal Borna Disease Virus (BDV) infection in rats leads to a neuronal loss in the cortex, hippocampus and cerebellum. Since BDV is a non-lytic infection in vitro, it has been suggested that activated microglia could contribute to neuronal damage. It is also conceivable that BDV-induced cell death triggers activation of microglia to remove cell debris. Although an overall temporal association between neuronal loss and microgliosis has been demonstrated in BDV-infected rats, it remains unclear if microgliosis precedes or results from neuronal damage. We investigated the timing of microglia activation and neuronal elimination in the dentate gyrus (DG) of the hippocampus. We found a significant increase in the number of ED1+ microglia cells as early as 10 days post infection (dpi) while a detectable loss of granule cells of the DG was not seen until 30 dpi. The data demonstrate for the first time that a non-lytic persistent virus infection of neurons activates microglia long before any measurable neuronal loss

Astrocytes play a key role in activation of microglia by persistent Borna disease virus infection

Neonatal Borna disease virus (BDV) infection of the rat brain is associated with microglial activation and damage to certain neuronal populations. Since persistent BDV infection of neurons is nonlytic in vitro, 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 brains remain unclear. Our previous studies have shown that activation of microglia by BDV in culture requires the presence of astrocytes as neither the virus nor BDV-infected neurons alone activate microglia. Here, we evaluated the mechanisms whereby astrocytes can contribute to activation of microglia in neuron-glia-microglia mixed cultures. We found that persistent infection of neuronal cells leads to activation of uninfected astrocytes as measured by elevated expression of RANTES. Activation of astrocytes then produces activation of microglia as evidenced by increased formation of round-shaped, MHCI-, MHCII- and IL-6-positive microglia cells. Our analysis of possible molecular mechanisms of activation of astrocytes and/or microglia in culture indicates that the mediators of activation may be soluble heat-resistant, low molecular weight factors. The findings indicate that astrocytes may mediate activation of microglia by BDV-infected neurons. The data are consistent with the hypothesis that microglia activation in the absence of neuronal damage may represent initial steps in the gradual neurodegeneration observed in brains of neonatally BDV-infected rats