Bornavirus Immunopathogenesis in Rodents: Models for Human Neurological Diseases

Journal of NeuroVirology (1999) 5, 604 ± 612 ã 1999 Journal of NeuroVirology, Inc. http://www.jneurovirology.com Bornavirus immunopathogenesis in rodents: models for human neurological diseases Thomas Briese1, Mady Hornig1 and W Ian Lipkin*,1 1Laboratory for the Study of Emerging Diseases, Department of Neurology, 3101 Gillespie Neuroscience Research Facility, University of California, Irvine, California, CA 92697-4292, USA 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 poten- tially linked to BDV infection. Two animal models have been established based on BDV infection of adult or neonatal Lewis rats. Analyis 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. Keywords: Borna disease virus; neurotropism; humoral and cellular immune response; Th1 ±Th2 shift; apoptosis; dopamine; cytokines Introduction Borna disease virus (BDV), the prototype of a new disorders and schizophrenia (Amsterdam et al, family, Bornaviridae, within the nonsegmented 1985; Bode et al, 1988, 1992, 1993; Fu et al, 1993; negative-strand RNA viruses, infects the central Kishi et al, 1995; Waltrip II et al, 1995), others have nervous system (CNS) of warmblooded animals to not succeeded in replicating these ®ndings (Iwata et cause behavioral disturbances reminiscent of au- al, 1998; Kubo et al, 1997; Lieb et al, 1997; Richt et tism, schizophrenia, and mood disorders (Lipkin et al, 1997). Here we review two rodent models of al, 1995). BDV is not lytic in vitro or in vivo, BDV infection that provide insight into mechanisms replicates at lower levels than most known viruses by which neurotropic viruses may impact CNS and is dissimilar in nucleic acid and protein development and function to effect complex dis- sequence to other infectious agents (de la Torre, turbances in behavior. 1994; Schneemann et al, 1995). The molecular biology of BDV is unusual in many respects including a nuclear localization for replication and Neurotropism and persistence transcription, overlap of open reading frames and transcription units, posttranscriptional modi®cation Neurotropism of BDV is likely to be multifactorial. of subgenomic RNAs, and marked conservation of The integrity of the humoral immune response is coding sequence across a wide variety of animal critical to restriction of virus to neural compart- species and tissue culture systems. Natural infec- ments (Stitz et al, 1998); however, replication is still tion has been con®rmed in horses, sheep, cattle, higher in limbic structures in animals with dogs, birds and cats. Primates can be infected compromised humoral immunity; thus, additional experimentally (Stitz et al, 1980). This wide host factors must contribute to neurotropism. One means range suggests that humans are likely to be by which preferential replication of BDV in limbic susceptible to BDV infection; however, there is no structures might occur is through restricted dis- consensus concerning the role of BDV in human tribution of the enzymatic machinery required for disease. Although some investigators report an its lifecycle. The phosphoprotein of BDV (P) is increased prevalence of BDV infection in mood predicted by analogy to phosphoproteins of other nonsegmented negative-strand RNA viruses to serve as a transcriptional activator (de la Torre, 1994; *Correspondence: WI Lipkin Received 3 March 1999; revised 21 May 1999; accepted 29 June Schneemann et al, 1995). It also contains potent 1999 nuclear localization signals (Shoya et al, 1998; Bornavirus rodent models of human CNS diseases TBrieseet al 605 Schwemmle et al, 1999) and interacts with two work by Stitz et al where passive transfer of other BDV proteins, the nucleoprotein and X- neutralizing antibodies resulted in limitation of protein to affect their intracellular distributions viral replication within the CNS (Stitz et al, 1998). (Schwemmle et al, 1998). Thus, P may also have Similar results have been reported in other viral additional functions related to nucleocasid assem- systems; for example, passive transfer of virus- bly and/or protein traf®cking within the cell. BDV P speci®c antibodies limits viral replication in the is phosphorylated primarily by the epsilon isotype CNS following infection with murine hepatitis virus of protein kinase C (PKCe) (Schwemmle et al, 1997). type-4 (Buchmeier et al, 1984) or measles virus Interestingly, the regional distributions of PKCe (Liebert et al, 1990), and induces clearance of virus (Saito et al, 1993) and BDV in rat brain (Narayan following infection with rabies (Dietzschold et al, et al, 1983a) are similar, suggesting the possibility 1992) or Sindbis virus (Levine et al, 1991). that the localization of PKCe, through its phosphor- ylation effects, may in¯uence the tropism of BDV for limbic circuitry. Adult Lewis rat infection In many CNS viral infections, the presence of an intact immune response results in either viral Bornavirus neuropathogenesis has been studied clearance or host mortality. This is not the case in primarily in adult immunocompetent rodents and BDV, where infection may persist in the presence of ungulates where infection results in dramatic a transient but robust immune response. Persistence disturbances in behavior, limbic circuitry, and may be due to induction of Th1 tolerance. Whereas monoamine neurotransmitter systems. These mod- lymphocytes isolated from brains of acutely in- els are intriguing; however, they are associated with fected rats have potent cytolytic activity, lympho- marked CNS in¯ammation, loss of brain mass and cytes from brains of chronically infected rats do not gliosis and may be less relevant to neuropsychiatric lyse BDV-infected target cells (Sobbe et al, 1997). diseases than those in neonatally infected rats Induction of BDV-speci®c tolerance in chronic where BDV induces subtle disturbances of behavior infection may re¯ect the timecourse for presentation and dysgenesis of the cerebellum and hippocampus of viral antigens in the thymus (Rubin et al, 1995). without robust in¯ammatory cell in®ltration. Alternatively, Th1 cells may become anergic or As in autism (Anderson, 1994; Ernst et al, 1997), undergo apoptosis due to presentation of BDV schizophrenia (Cooper et al, 1991), and mood antigens in brain without essential costimulatory disorders (Hamner and Diamond, 1996; Kelsoe et signals (Karpas et al, 1994; Khoury et al, 1995; al, 1996; Partonen, 1996), disorders of movement Schwartz, 1992). Support for the latter hypothesis is and behavior in adult BD rats are linked to distinct found in the observation that apoptosis of perivas- changes in CNS dopamine systems (Solbrig et al, cular in¯ammatory cells is most apparent at 5 ± 6 1994, 1995, 1996a,b, 1998) and may be further weeks post infection (p.i.), coincident with the onset linked to serotonin abnormalities (Solbrig et al, of decline in encephalitis (Hatalski et al, 1998a). 1995). The immune-mediated disorder in adult In an effort to explore differences in host gene infected rats presents clinically as hyperactivity expression during persistent infection that might be and exaggerated startle responses 10 ± 14 days after linked to tolerance, subtractive cloning methods intracerebral infection (Narayan et al, 1983a). The were applied to analysis of RNA from brains of acute phase coincides with in®ltration of mono- acute and persistent adult infected rats. The cytes into the brain, particularly in areas of high persistently infected rats had a dramatic increase viral burden including the hippocampus, amygdala in mRNAs encoding immunoglobulin ± a ®nding and other limbic structures (Carbone et al, 1987). that suggested that Th1 tolerance might re¯ect a Two to three weeks later, rats show high grade Th1 ±Th2 shift in the immune response. This stereotyped motor behaviors (the continuous repeti- hypothesis was con®rmed by RNase protection tion of behavioral elements such as snif®ng, assays that demonstrated a shift in the brain chewing, scratching, grooming, and self-biting), cytokine mRNA pro®le from Th1 ±Th2 cytokines dyskinesias, dystonias, and ¯exed seated postures and an isotype switch in peripheral blood from IgG (Solbrig et al, 1994), in parallel with the widespread to IgE (Hatalski et al, 1998a,b). Although the distribution of virus in limbic and prefrontal enhanced humoral immune response in chronic circuits. Five to ten per cent of animals become disease does not promote viral clearance, it may obese, achieving body weights up to 300% of play an important role in limiting viral gene normal (Ludwig et al, 1988). expression (Hatalski et al, 1998a). Complementary Central dopamine systems of adult-infected BD work by Hatalski et al (1998b) in the chronic phase animals are more sensitive to dopamine agonists of BD reported increases in intra-CNS production of and antagonists than normal rats. Infected animals IgG antibodies that parallel increases of antibodies have increased locomotor and stereotypic behavior with neutralizing activity against BDV in peripheral following administration of the mixed-acting dopa- blood. De®nitive evidence that humoral immunity mine agonist, dextroamphetamine (Solbrig et al, contributes to BDV tropism emerged from recent 1994). Similarly, enhanced locomotion and stereo- Bornavirus rodent models of human CNS

Load more