MECHANISMS OF NEUROPATHOGENESIS IN BORNA DISEASE

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DESCRIPTION (Applicant's Abstract): Borna disease virus (BDV) is a newly classified RNA virus that infects the CNS of warm blooded animals to cause disturbances of movement and behavior. Natural infection has been confirmed only in horses, sheep, cattle, birds, and cats; however, primates can be infected experimentally. Although the data remain controversial, several investigators have reported evidence of infection in schizophrenia and affective disorders. Most previous work in BDV pathogenesis has focused on infected adult immunocompetent rodents and ungulates where dramatic disturbances in behavior, limbic circuitry, and monoamine neurotransmitter systems are reminiscent of aspects of some neuropsychiatric syndromes (autism, schizophrenia, or bipolar disorder). While these models are intriguing they are associated with CNS inflammation, marked loss of brain mass and gliosis and may be less relevant to neuropsychiatric diseases than those in neonatally infected rats where BDV induces subtle disturbances of behavior, and hippocampal and cerebellar dysgenesis without inflammatory cell infiltration. The broad objectives of this project will be to: (1) determine the mechanisms by which viral infections alter CNS architecture and function without invoking infiltrating inflammatory elements and (2) establish and investigate nonhuman primate models for BDV infection. Whereas models for persistent tolerant infection of neonatal rats have been described, nonhuman primate studies have been pursued only in acutely infected adult rhesus macaques. Studies proposed here will clarify whether primates can be infected in the perinatal period and, if so, whether the clinical, behavioral, and neuropathologic sequelae are consistent with human psychiatric disease. The investigators hypothesize that perinatal infections of Rhesus monkeys will manifest as subtle neurobehavioral and neuropathologic disturbances in a primate counterpart to the neonatal rat model of persistent BDV infection. They further propose that elucidation of the pathogenesis of such neurologic dysfunction through more extensive studies of neonatal BDV infection of rats will provide critical information about mechanisms of viral-CNS interactions that will then permit more focused, informed investigations in humans and nonhuman primates. Specific aims in the neonatal rat model are: i) characterize the nature of the behavioral, cognitive, and motor deficits; ii) examine the neuropathology associated with the neurologic abnormalities; iii) evaluate changes in levels of cytokines as potential mediators of BDV-related damage; iv) discern whether apoptosis contributes to the neuropathology observed after neonatal infections and v) assess regional changes in neurotransmitter and neuroendocrine systems following neonatal BDV infection. The specific aims of the primate component of this application are to: 1) establish nonhuman primate models for BDV CNS infection using fetal and weanling Rhesus macaques; 2) determine the timecourse of the humoral immune response to BDV in infected fetal (intraventricular infection in utero) and weanling (intracerebral or intranasal infection) Rhesus macaques; 3) assess whether BDV nuclei acids can be detected in peripheral white blood cells (WBC) of infected Rhesus macaques; in the event that WBC are found to contain BDV nucleic acids can be detected in peripheral white blood cells (WBC) or infected Rhesus macaques; and in the event that WBC are found to contain BDV nucleic acids, to determine the distribution of BDV nucleic acids with respect to cell type and timecourse after infection; 4) define the hematologic, chemical, and virologic profile of cerebrospinal fluid (CFS) in infected fetal and weanling Rhesus macaques; 5) characterize the nature of any neurobehavioral, socioemotional, or motor deficits, and 6) evaluate neuropathology through in vivo (MRI and PET brain imaging) and postmortem analyses.