TY - JOUR
T1 - Astrocytes play a key role in activation of microglia by persistent Borna disease virus infection
AU - Ovanesov, Mikhail V.
AU - Ayhan, Yavuz
AU - Wolbert, Candie
AU - Moldovan, Krisztina
AU - Sauder, Christian
AU - Pletnikov, Mikhail V.
N1 - Funding Information:
The study was supported by R01MH048948 (MVP). The authors also want to express their gratitude to Drs Ellen Silbergeld and Jeniffer Nyland (JH Bloomberg School of Public Health) for their generous help with multiplex assays. John Hiscott, PhD, McGill University, Montreal, Canada, Dr Peter Collins and Dr Ulla Buchholz, NIH, Bethesda, MD, USA for their generous permission to work with and donation of VSV-GFP virus. The authors would like to thank Dr Friedemann Weber (University of Freiburg, Freiburg, Germany) for his insightful discussion of the study.
PY - 2008/11/11
Y1 - 2008/11/11
N2 - 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.
AB - 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.
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U2 - 10.1186/1742-2094-5-50
DO - 10.1186/1742-2094-5-50
M3 - Article
C2 - 19014432
AN - SCOPUS:57149145659
SN - 1742-2094
VL - 5
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
M1 - 50
ER -