Studies on the heterogeneity in the correlation between Borna disease virus location in the central nervous system(CNS) and induced CNS pathogenesis

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Borna disease virus(BDV) is a highly neurotropic, negative-, single-stranded RNA virus and is the etiological agent of Borna disease, encephalitis in horses and sheep. Infection with BDV in humans, especially in some of the patients with psychiatric disorders, was reported. In fact, BDV signals were identified in some of the autopsied brains from the BDV-seropositive patients. The objective in this study is to analyze the BDV virulence at in vivo and in vitro levels as well as molecular level in order to clarify the mechanism of BDV-induced pathogenesis at the central nervous system. Studies using neuronal cell cultures, revealed 1)the interaction between BDV p24 phosphoprotein (P) and multi-functional protein HMGB1 (also named amphoterin) ; 2)blocking of functions of HMGB1 by the interaction with P protein ; and 3)significant decrease of host anti-stress (such as heating) responses. In addition, we found that neurological symptoms were induced in the rats by stress (intraperitoneal injection with LPS) under the condition with persistent infection with BDV. Further, we prepared transgenic mice expressing BDVP protein under the GFAP promoter in the brain and found that the transgenic mice showed aggressive behavior and significant impairement of spatial reference memory, but no significant effect in the locomotor activity. These transgenic mice also showed the significant decreases in the levels of brain-derived neurotrophic factor(BDNF), synapse density, serotonin receptors (5-THR_<1A> and 5-THR_<1B>) in the brains. Thus, using several model systems, it was clarified that the CNS pathogenesis could appear by the persistent infection with BDV in the CNS.