title: Astrocytes play a key role in activation of microglia by persistent Borna disease virus infection.
abstract: 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ovanesov@gmail.com
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Ovanesov
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Ayhan
authors.forename: Candie
authors.initials: C
authors.lastname: Wolbert
authors.forename: Krisztina
authors.initials: K
authors.lastname: Moldovan
authors.forename: Christian
authors.initials: C
authors.lastname: Sauder
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Pletnikov
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000821:virology; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001890:Borna Disease / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D001891:Borna disease virus / Q000502:physiology; D001921:Brain / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D018920:Coculture Techniques; D004660:Encephalitis / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D005911:Gliosis / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D017628:Microglia / Q000276:immunology* / Q000821:virology; D009410:Nerve Degeneration / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D009474:Neurons / Q000276:immunology / Q000473:pathology / Q000821:virology; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D015415:Biomarkers; D018946:Chemokine CCL5; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D015850:Interleukin-6