Primary psychosis and Borna disease virus infection in Lithuania: a case control study.

BACKGROUND: The hypothesis that microbial infections may be linked to mental disorders has long been addressed for Borna disease virus (BDV), but clinical and epidemiological evidence remained inconsistent due to non-conformities in detection methods. BDV circulating immune complexes (CIC) were shown to exceed the prevalence of serum antibodies alone and to comparably screen for infection in Europe (DE, CZ, IT), the Middle East (IR) and Asia (CN), still seeking general acceptance. METHODS: We used CIC and antigen (Ag) tests to investigate BDV infection in Lithuania through a case-control study design comparing in-patients suffering of primary psychosis with blood donors. One hundred and six acutely psychotic in-patients with no physical illness, consecutively admitted to the regional mental hospital, and 98 blood donors from the Blood Donation Centre, Lithuania, were enrolled in the study. The severity of psychosis was assessed twice, prior and after acute antipsychotic therapy, by the Brief Psychiatric Rating Scale (BPRS). BDV-CIC and Ag markers were tested once after therapy was terminated. RESULTS: What we found was a significantly higher prevalence of CIC, indicating a chronic BDV infection, in patients with treated primary psychosis than in blood donor controls (39.6 % vs. 22.4 %, respectively). Free BDV Ag, indicating currently active infection, did not show significant differences among study groups. Higher severity of psychosis prior to treatment was inversely correlated to the presence of BDV Ag (42.6 vs. 34.1 BPRS, respectively; p = 0.022). CONCLUSIONS: The study concluded significantly higher BDV infection rates in psychotic than in healthy Lithuanians, thus supporting similar global trends for other mental disorders. The study raised awareness to consider the integration of BDV infection surveillance in psychiatry research in the future.

[Schizophrenia--a mild encephalitis?]. / Schizophrenie--eine milde Enzephalitis?

The mild encephalitis (ME) hypothesis describes a subgroup of severe psychiatric disorders, with a focus on a subgroup of schizophrenias, in which low-level neuroinflammation (LLNI) represents the core in pathogenesis. LLNI is increasingly recognised in experimental neuroimmunology and is in principle able to explain various types of psychopathology. Epidemiology and course of schizophrenia are well compatible with the ME hypothesis, indirectly indicating that the ME subgroup may be rather large. With the ME model connected is a set of three contributing factors: genes, environment (especially infectious agents) and the immune system. The type of psychopathology observed in the individual case may heavily depend upon other conditions, e. g. pre-existing vulnerabilities. The first large-scale epidemiological study in psychiatry identified two factors during lifetime, severe infectious diseases and autoimmune diseases, as risk factors. This and clinical findings more and more support the ME hypothesis, e. g., activated monocytes or proteome changes in blood and slight CSF pathologies in more than 60 % of therapy-resistant schizophrenia, or activated microglia and dysconnectivity in neuroimaging.

The use of peptide arrays for the characterization of monospecific antibody repertoires from polyclonal sera of psychiatric patients suspected of infection by Borna Disease Virus.

Borna Disease Virus (BDV) is suspected to infect humans and to be associated with psychiatric disorders. To this date, BDV-reactive antibodies provide the only reliable markers to diagnose human BDV infection. Their diagnostic value, however, was recently questioned by the observation that these antibodies recognize BDV antigen with only low avidity, a typical feature of cross-reacting antibodies. This raised the possibility that the human BDV-reactive antibodies were triggered by other pathogens than BDV. The recent establishment of a peptide array-based screening test allowed the further characterization of these antibodies. It revealed the presence of small amounts of BDV-reactive antibodies in crude human sera that specifically recognized various epitopes of three major BDV proteins. Most importantly, the purified epitope-specific antibodies were shown to bind to BDV antigen with high avidity when assayed by conventional immunofluorescence assay (IFA) or by Western blot. These results are compatible with the view that the presence of BDV-reactive antibodies in human sera reflects an infection with BDV, although the poor affinity maturation remains unexplained. Furthermore, it demonstrates that peptide array-based screening tests are a reliable system for identifying monospecific antibodies from human polyclonal sera with high specificity and sensitivity.

Glial expression of Borna disease virus phosphoprotein induces behavioral and neurological abnormalities in transgenic mice.

One hypothesis for the etiology of behavioral disorders is that infection by a virus induces neuronal cell dysfunctions resulting in a wide range of behavioral abnormalities. However, a direct linkage between viral infections and neurobehavioral disturbances associated with human psychiatric disorders has not been identified. Here, we show that transgenic mice expressing the phosphoprotein (P) of Borna disease virus (BDV) in glial cells develop behavioral abnormalities, such as enhanced intermale aggressiveness, hyperactivity, and spatial reference memory deficit. We demonstrate that the transgenic brains exhibit a significant reduction in brain-derived neurotrophic factor and serotonin receptor expression, as well as a marked decrease in synaptic density. These results demonstrate that glial expression of BDV P leads to behavioral and neurobiological disturbances resembling those in BDV-infected animals. Furthermore, the lack of reactive astrocytosis and neuronal degeneration in the brains indicates that P can directly induce glial cell dysfunction and also suggests that the transgenic mice may exhibit neuropathological and neurophysiological abnormalities resembling those of psychiatric patients. Our results provide a new insight to explore the relationship between viral infections and neurobehavioral disorders.

Borna disease virus infection of the neonatal rat: developmental brain injury model of autism spectrum disorders.

Autism spectrum disorders (ASD) have been the focus of a great deal of research and clinical speculation. This intense interest relates to both the perplexing pathogenesis and devastating consequences of these disorders. One of the obstacles to understanding the pathogenesis of autism and its efficient treatment has been the paucity of animal models that could be used for hypotheses-driven mechanistic studies of abnormal brain and behavior development and for the pre-clinical testing novel pharmacological treatments. The present review provides a detailed analysis of a new animal model of ASD. This model utilizes neonatal Borna disease virus (BDV) infection of the rat brain as a unique experimental teratogen to study the pathogenesis of neurodevelopmental damage. For more than a decade, studies of the BDV animal model have yielded much insight into the pathogenic processes of abnormal brain development and resulting autistic-like behavioral abnormalities in rats. The most recent experiments demonstrate the utility of the BDV model for studying the pathophysiological mechanisms of the gene-environment interaction that determines differential disease outcomes and variability in responses to treatments.

Borna disease virus and psychiatry.

Borna disease virus (BDV), a noncytolytic neurotropic nonsegmented negative-stranded RNA virus with a wide geographic distribution, infects several vertebrate animal species and causes an immune-mediated central nervous system (CNS) disease with various manifestations, depending on both host and viral factors. In animal infections, BDV can persist in the CNS and induce alterations in brain cell functions, neurodevelopmental abnormalities and behavioral disturbances. An association between BDV and psychiatric disorders (essentially schizophrenia and affective disorders) has been suggested by some serologic and molecular studies but further investigations are required to substantiate the possible contribution of this virus to the pathogenesis of these disorders.

Learning deficits in mice with persistent Borna disease virus infection of the CNS associated with elevated chemokine expression.

Borna disease virus (BDV) is a highly neurotropic RNA virus that causes a CD8(+) T cell-mediated neurological disease in certain mouse strains. We established asymptomatic persistent central nervous system (CNS) infections in mutant C57BL/10J mice that lack functional CD8(+) T cells. When analyzed at adult age for spatial learning abilities in a water maze, BDV-infected mice showed slightly impaired escape performance while their exploratory behavior in an openfield test was indistinguishable from uninfected control mice. Histological and molecular biological analysis revealed extensive viral spread throughout the CNS of infected animals. Most neurons of the hippocampus contained viral antigen, but there was no overt loss of neurons from this structure. We found almost unchanged levels of the proinflammatory cytokines IL-1beta and TNF-alpha, but clearly increased levels of the chemokines IP-10 and RANTES in brains of infected mice. Re-examination of water maze data revealed that only infected mice with IP-10 transcript levels above a certain threshold showed impaired performance, whereas the performance of infected mice with lower IP-10 levels was indistinguishable from uninfected controls. This suggests that BDV infection can disturb the function of the mammalian CNS without causing overt neuronal loss, and that the magnitude of virus-induced chemokine production in the CNS correlates with the degree of impairment.

Borna disease virus infection in psychiatric patients: are we on the right track?

Animals infected with Borna disease virus (BDV) typically present with neurological dysfunction including behavioural abnormalities. Seroepidemiological surveys suggested that BDV infection can occur in human beings and is associated with mental disorders. Partly contradictory results from studies employing RT-PCR and serological screening led to debate over whether BDV can infect people at all. Critical evaluation of available data led to doubts about the diagnostic value of RT-PCR-based test results. A more consistent picture has emerged from serological studies because seropositive cases were found more frequently among psychiatric patients than among normal controls, supporting the notion that BDV might indeed be responsible for some psychiatric disorders. This view is now challenged by the observation that human BDV-reactive antibodies are of low avidity and might therefore represent cross-reacting antibodies. It remains to be shown whether these antibodies are indeed induced by BDV or by related antigens of unknown identity.

Bornavirus immunopathogenesis in rodents: models for human neurological diseases.

Although the question of human BDV infection remains to be resolved, burgeoning interest in this unique pathogen has provided tools for exploring the pharmacology and neurochemistry of neuropsychiatric disorders potentially linked to BDV infection. Two animal models have been established based on BDV infection of adult or neonatal Lewis rats. Analysis of these models is already yielding insights into mechanisms by which neurotropic agents and/or immune factors may impact developing or mature CNS circuitry to effect complex disturbances in movement and behavior.

Borna disease virus-induced hippocampal dentate gyrus damage is associated with spatial learning and memory deficits.

In neonatally inoculated rats, Borna disease virus (BDV) leads to a persistent infection of the brain in the absence of an inflammatory response and is associated with neuroanatomic, developmental, physiologic, and behavioral abnormalities. One of the most dramatic sites of BDV-associated damage in the neonatal rat brain is the dentate gyrus, a neuroanatomic region believed to play a major role in spatial learning and memory. The absence of a generalized inflammatory response to neonatal BDV infection permits direct effects of viral damage to the dentate gyrus to be examined. In this report, neonatally BDV-infected rats at various stages of dentate gyrus degeneration were evaluated in the Morris water maze, a swimming test that assesses the rats' capacity to navigate by visual cues. Our data demonstrate progressive spatial learning and memory deficits in BDV-infected rats that coincided with a gradual decline in the estimated hippocampal dentate gyrus neuron density.

A viro-psycho-immunological disease-model of a subtype affective disorder.

Borna Disease Virus (BDV) infections are widespread in animal species. This neurotropic, negative and single-stranded enveloped RNA virus spreads via axonal and transsynaptic pathways quite specifically into olfactoric and limbic structures. The symptoms in BDV-infected animals range from unapparent or subtle clinical manifestations to fatal neurological disorders. The severe and fulminant course of the infection, which is often accompanied by neurobehavioral and "emotional" disturbances, occurs sporadically and, at least in experimentally infected animals (rats), is thought to be mediated by immunopathology. Increases in serum-BDV antibodies have also been detected in neuropsychiatric patients. In addition, viral antigen and viral RNA have been observed in acutely ill major depressive patients, leading to the conclusion that BDV was causally related to psychiatric disorders, in particular to affective disorders. A number of studies have meanwhile furnished evidence of abnormal immune functions in mentally ill patients. In addition, stress has been shown to decrease immune responses to viral infections. On the basis of these findings it is hypothesized that human BDV infection represents a co-factor in the development or course of psychiatric diseases. Stress may cause immunosuppression and thus induce activation of persisting BDV in the limbic system, resulting in an inflammatory reaction of these structures. These neuropathological changes might influence the serotonergic or dopaminergic neurotransmitter systems. In addition, a specific affinity of BDV structural elements for aspartate and glutamate receptors in the hippocampal formation might directly induce an imbalance of these transmitter system interactions, causing affective and behavioral disturbances. The possible interactions between stress-induced immunosuppression, BDV infection and affective disorders in humans, and the theoretical and clinical aspects of this concept are discussed.

Positive and negative syndromes, and Borna disease virus infection in schizophrenia.

The relationship between Borna disease virus (BDV) infection and positive and negative syndromes in schizophrenia was investigated. By nested RT-PCR and Western blotting, BDV-specific RNA and anti-BDV antibodies were examined in blood from 67 schizophrenic patients (DSM-III-R) in Japan, and the psychometric properties of the Positive and Negative Syndrome Scale (PANSS) were analyzed. There were significant (p < 0.05) differences in the composite index denoting the positive minus negative difference indicating a dominant contribution by negative items, and the proportion of negative type (positive minus negative value below zero) patients, between patients positive and negative for anti-BDV p24 antibodies. It is possible that BDV infection with induction of BDV p24 antibodies may be associated with negative syndromes in schizophrenic patients.

Cocaine sensitivity in Borna disease virus-infected rats.

Borna disease virus (BDV) is a neurotropic RNA virus that infects warm-blooded animals to cause disturbances of movement and behavior. Studies in infected rats have demonstrated behavioral sensitivity to direct and indirect dopamine (DA) agonists; however, behavioral responses to an indirect DA agonist with a pure presynaptic effect have not been analyzed. Rats infected with BDV had an enhanced response to the locomotor, behavioral, and convulsant effects of cocaine at intraperitoneal doses of 7.5, 15, and 30 mg/kg. The basis for this sensitivity was examined by striatal DA uptake site and D1 and D2 receptor autoradiography. DA uptake sites, labeled with [3H] mazindol, were reduced in medial caudate-putamen (CP), and binding of [3H] raclopride to D2 sites was reduced in medial and ventral striatal areas. The topography of DA uptake and D2 site loss corresponds to the distribution of BDV viral nucleic acids in CP and overlays the medial striatal areas that function in conditioned reward. The BDV-infected rat provides a model of cocaine sensitivity based on viral central nervous system infection and may have relevance for studies of cocaine abuse in the context of other viral encephalopathies, such as those associated with HIV infection.

["In the beginning the horse is sad"--a historical abstract of Borna disease]. / "Das Pferd ist anfänglich traurig"--ein geschichtlicher Abriss der Bornaschen Krankheit.

Borna disease has a 230 year old history, having first been described in 1766. Scientific studies of borna disease began in 1895. Ernst Joest and Kurt Degen found inclusion bodies within ganglion cells of the hippocampus in 1909. Wilhelm Zwick successfully transmitted Borna disease to rabbits in 1924. This marked the beginning of systematic studies to determine the pathogenesis of Borna disease as it is now understood in the 1990s.

[Expanded nuclear magnetic resonance studies in Borna disease virus seropositive psychiatric patients and control probands]. / Erweiterte kernspintomographische Untersuchungen bei Borna-disease-Virus -seropositiven psychiatrischen Patienten und Kontrollen.

There is growing evidence, that Borna Disease virus (BDV) or a variant may cause neuropsychiatric disorders in humans. The presence of specific BDV serum antibodies indicates an earlier contact with BDV. Earlier MRI results showing a raised prevalence of white matter lesions in BDV-seropositive psychiatric patients, possibly indicating encephalitic lesions, are not confirmed in this extended study, however in BDV-seropositive psychiatric patients the occurrence of cerebral atrophy seems to be more frequent, a finding compatible with hydrocephalus e vacuo found in animals after BDV-encephalitis. Because encephalitic lesions in BD are predominantly found in the gray matter of the brain, which is hardly visualized by MRI, the failure to detect lesions in BDV-seropositive patients could be due to methodological problems.