Significance Borna disease virus (BDV) infects a broad range of warmblooded species (mammals and birds) to cause neurologic dysfunction. Evidence from several laboratories indicates that BDV may be associated with human neuro-psychiatric disorders. Preferential infection of limbic circuitry, disturbances in D2 and D3 neurotransmitter systems, and the behavioral and motor disturbances that accompany acute BDV infection in adult, immunocompetent rodents and ungulates suggest parallels with serious psychiatric disorders such as schizophrenia, bipolar affective disorder, and autism. Attempts to demonstrate BDV infections in humans through serologic and molecular analysis of peripheral blood samples have produced inconsistent results. Objectives We hypothesize that perinatal infections of rhesus macaques will manifest as subtle neurobehavioral and neuropathologic disturbances in a primate counter part to the neonatal rat model of persistent BDV infection. The objective of this pilot study is to develop a nonhuman primate model of persistent BDV infection, and determine if the clinical, behavioral and neuropathologic sequelae are consistent with human psychiatric disease. Results Intracranial inoculation of BDV in 2 juvenile rhesus macaques resulted in infection and fatal clinical disease at 5 and 8 weeks pi, respectively. Both animals developed the acute, encephalitic form of BDV infection, indicating that animals of this age are already immunologically mature enough to preclude immunologic tolerance and persistent infection. Both animals developed strong humeral immune responses to BDV-specific antigens, thus providing valuable primate reagents for refining and validating available serologic tests. In one animal, preliminary PCR assays have detected viral nucleic acids in samples of peripheral blood mononuclear cells. Two neonatal rhesus were inoculated intranasally. One developed encephalitis and was euthanatized 9 week p.i. The second neonate did not become infected following intranasal inoculation. To better approximate the immune competence of the neonatal rat, intraventricular inoculation of 2 fetuses (~90-100 day gestation) have been pe rformed in utero, using ultra-sound guided techniques. One pregnancy resulted in live-born infant with severe congenital abnormalities and neurologic deficits that was euthanatized at 5 days of age. BDV was detected in tissues and the infant had high titer of anti-BDV antibodies. The second pregnancy resulted in a near term fetal loss. Ultrasound guided inoculation (IP or IC) was performed on 2 additional fetuses of 50 days gestation. The IP inoculation resulted in fetal death ~60 days p.i. The second fetus (IC inoc) is viable and appears to be developing normally at ~43 days p.i. Future Directions The last pregnancy will be allowed to go to term, and the neonate will be monitored for persistent BDV infection. Other strategies for inducing immune tolerance to BDV in macaques will be investigated. KEY WORDS borna disease virus, neurologic dysfunction FUNDING NIH RR00169 Pilot Study - In Progress
Showing the most recent 10 out of 408 publications
