scholarly journals CD8+ T Lymphocytes Mediate Borna Disease Virus-Induced Immunopathology Independently of Perforin

2001 ◽  
Vol 75 (21) ◽  
pp. 10460-10466 ◽  
Author(s):  
Jürgen Hausmann ◽  
Karin Schamel ◽  
Peter Staeheli
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Disease Virus ◽  
Target Cells ◽  
Wild Type ◽  
Pathogenic Potential ◽  
Borna Disease Virus ◽  
Viral Spread ◽  
Deficient Mice ◽  
Borna Disease

ABSTRACT Perforin-mediated lysis of target cells is the major antiviral effector mechanism of CD8+ T lymphocytes. We have analyzed the role of perforin in a mouse model for CD8+T-cell-mediated central nervous system (CNS) immunopathology induced by Borna disease virus. When a defective perforin gene was introduced into the genetic background of the Borna disease-susceptible mouse strain MRL, the resulting perforin-deficient mice developed strong neurological disease in response to infection indistinguishable from that of their perforin-expressing littermates. The onset of disease was slightly delayed. Brains of diseased perforin-deficient mice showed similar amounts and a similar distribution of CD8+ T cells as wild-type animals. Perforin deficiency had no impact on the kinetics of viral spread through the CNS. Unlike brain lymphocytes from diseased wild-type mice, lymphocytes from perforin-deficient MRL mice showed no in vitro cytolytic activity towards target cells expressing the nucleoprotein of Borna disease virus. Taken together, these results demonstrate that CD8+ T cells mediate Borna disease independent of perforin. They further suggest that the pathogenic potential of CNS-infiltrating CD8+ T cells does not primarily reside in their lytic activity but rather in other functions.

scholarly journals CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

2005 ◽  
Vol 79 (21) ◽  
pp. 13509-13518 ◽  
Author(s):  
Jürgen Hausmann ◽  
Axel Pagenstecher ◽  
Karen Baur ◽  
Kirsten Richter ◽  
Hanns-Joachim Rziha ◽  
...  
Keyword(s):  
T Cells ◽  
Disease Virus ◽  
Cd8 T Cells ◽  
Gamma Interferon ◽  
Wild Type ◽  
Borna Disease Virus ◽  
Ifn Γ ◽  
The Brain ◽  
Deficient Mice ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) frequently causes meningoencephalitis and fatal neurological disease in young but not old mice of strain MRL. Disease does not result from the virus-induced destruction of infected neurons. Rather, it is mediated by H-2 k -restricted antiviral CD8 T cells that recognize a peptide derived from the BDV nucleoprotein N. Persistent BDV infection in mice is not spontaneously cleared. We report here that N-specific vaccination can protect wild-type MRL mice but not mutant MRL mice lacking gamma interferon (IFN-γ) from persistent infection with BDV. Furthermore, we observed a significant degree of resistance of old MRL mice to persistent BDV infection that depended on the presence of CD8 T cells. We found that virus initially infected hippocampal neurons around 2 weeks after intracerebral infection but was eventually cleared in most wild-type MRL mice. Unexpectedly, young as well as old IFN-γ-deficient MRL mice were completely susceptible to infection with BDV. Moreover, neurons in the CA1 region of the hippocampus were severely damaged in most diseased IFN-γ-deficient mice but not in wild-type mice. Furthermore, large numbers of eosinophils were present in the inflamed brains of IFN-γ-deficient mice but not in those of wild-type mice, presumably because of increased intracerebral synthesis of interleukin-13 and the chemokines CCL1 and CCL11, which can attract eosinophils. These results demonstrate that IFN-γ plays a central role in host resistance against infection of the central nervous system with BDV and in clearance of BDV from neurons. They further indicate that IFN-γ may function as a neuroprotective factor that can limit the loss of neurons in the course of antiviral immune responses in the brain.

scholarly journals Virus-Specific CD4+ T Cells Eliminate Borna Disease Virus from the Brain via Induction of Cytotoxic CD8+T Cells

1998 ◽  
Vol 72 (5) ◽  
pp. 4387-4395 ◽  
Author(s):  
Kerstin Nöske ◽  
Thomas Bilzer ◽  
Oliver Planz ◽  
Lothar Stitz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Disease Virus ◽  
Target Cells ◽  
Borna Disease Virus ◽  
Infected Control ◽  
Low Level ◽  
The Brain ◽  
Borna Disease

ABSTRACT Persistent Borna disease virus infection of the brain can be prevented by treatment of naive rats with a virus-specific CD4+ T-cell line prior to infection. In rats receiving this treatment, only a transient low-level encephalitis was seen compared to an increasingly inflammatory reaction in untreated infected control rats. Virus replication was found in the brain for several days after infection before the virus was cleared from the central nervous system. The loss of infectivity from the brain was confirmed by negative results by reverse transcription-PCR with primers for mRNA, by in situ hybridization for both genomic and mRNA, and by immunohistology. Most importantly, in vitro assays revealed that the T-cell line used for transfusion had no cytotoxic capacity. The kinetics of virus clearance were paralleled by the appearance of CD8+ T cells and the expression of perforin in the brain. Testing of lymphocytes isolated from the brains of CD4+T-cell-treated rats after challenge revealed high cytotoxic activity due to the presence of CD8+ cytotoxic T cells at time points when brain lymphocytes from infected control rats induced low-level cytolysis of target cells. Neutralizing antiviral antibodies and gamma interferon were shown not to be involved in the elimination of virus from the brain.

scholarly journals Identification of the Immunodominant H-2Kk-Restricted Cytotoxic T-Cell Epitope in the Borna Disease Virus Nucleoprotein

2001 ◽  
Vol 75 (18) ◽  
pp. 8579-8588 ◽  
Author(s):  
Karin Schamel ◽  
Peter Staeheli ◽  
Jürgen Hausmann
Keyword(s):  
T Cell ◽  
Disease Virus ◽  
Neurological Disease ◽  
Cell Epitope ◽  
Cytotoxic T Cell ◽  
Target Cells ◽  
Wild Type ◽  
Borna Disease Virus ◽  
Ctl Epitope ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV)-induced immunopathology in mice is most prominent in strains carrying the major histocompatibility complexH-2k allele and is mediated by CD8+ T cells that are directed against the viral nucleoprotein p40. We now identified the highly conserved octamer peptide TELEISSI, located between amino acid residues 129 and 136 of BDV p40, as a potent H-2Kk-restricted cytotoxic T-cell (CTL) epitope. When added to the culture medium of L929 target cells, TELEISSI conferred sensitivity to lysis by CTLs isolated from brains of BDV-infected MRL mice with acute neurological disease. Vaccinia virus-mediated expression of a p40 variant with mutations in the two Kk-specific anchor residues of the TELEISSI peptide (p40E130K,I136T) did not sensitize L929 target cells for lysis by BDV-specific CTLs, whereas expression of wild-type p40 did. Furthermore, unlike vaccination with wild-type p40, vaccination of persistently infected symptomless B10.BR mice with p40E130K,I136T did not result in central nervous system inflammation and neurological disease. These results demonstrate that TELEISSI is the immunodominant CTL epitope of BDV p40 inH-2k mice.

scholarly journals Borna Disease Virus Accelerates Inflammation and Disease Associated with Transgenic Expression of Interleukin-12 in the Central Nervous System

2002 ◽  
Vol 76 (23) ◽  
pp. 12223-12232 ◽  
Author(s):  
Susanna Freude ◽  
Jürgen Hausmann ◽  
Markus Hofer ◽  
Ngan Pham-Mitchell ◽  
Iain L. Campbell ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Transgenic Mice ◽  
Disease Virus ◽  
Biologically Active ◽  
Interleukin 12 ◽  
Wild Type ◽  
Borna Disease Virus ◽  
The Central Nervous System ◽  
Borna Disease

ABSTRACT Targeted expression of biologically active interleukin-12 (IL-12) in astrocytes of the central nervous system (CNS) results in spontaneous neuroimmunological disease of aged mice. Borna disease virus (BDV) can readily multiply in the mouse CNS but does not trigger disease in most strains. Here we show that a large percentage of IL-12 transgenic mice developed severe ataxia within 5 to 10 weeks after infection with BDV. By contrast, no disease developed in mock-infected IL-12 transgenic and wild-type mice until 4 months of age. Neurological symptoms were rare in infected wild-type animals, and if they occurred, these were milder and appeared later. Histological analyses showed that the cerebellum of infected IL-12 transgenic mice, which is the brain region with strongest transgene expression, contained large numbers of CD4+ and CD8+ T cells as well as lower numbers of B cells, whereas other parts of the CNS showed only mild infiltration by lymphocytes. The cerebellum of diseased mice further showed severe astrogliosis, calcifications and signs of neurodegeneration. BDV antigen and nucleic acids were present in lower amounts in the inflamed cerebellum of infected transgenic mice than in the noninflamed cerebellum of infected wild-type littermates, suggesting that IL-12 or IL-12-induced cytokines exhibited antiviral activity. We propose that BDV infection accelerates the frequency by which immune cells such as lymphocytes and NK cells enter the CNS and then respond to IL-12 present in the local milieu causing disease. Our results illustrate that infection of the CNS with a virus that is benign in certain hosts can be harmful in such normally disease-resistant hosts if the tissue is unfavorably preconditioned by proinflammatory cytokines.

The Borna disease virus (BoDV) 2 nucleoprotein is a conspecific protein that enhances BoDV-1 RNA-dependent RNA polymerase activity

2021 ◽  
Author(s):  
Takehiro Kanda ◽  
Masayuki Horie ◽  
Yumiko Komatsu ◽  
Keizo Tomonaga
Keyword(s):  
Disease Virus ◽  
Reverse Genetics ◽  
Rna Virus ◽  
Polymerase Activity ◽  
Wild Type ◽  
Borna Disease Virus ◽  
Rna Polymerase Activity ◽  
Nucleoprotein N ◽  
Transcription And Replication ◽  
Borna Disease

An RNA virus-based episomal vector (REVec) based on Borna disease virus 1 (BoDV-1) is a promising viral vector that achieves stable and long-term gene expression in transduced cells. However, the onerous procedure of reverse genetics used to generate a REVec is one of the challenges that must be overcome to make REVec technologies practical for use. In this study, to resolve the problems posed by reverse genetics, we focused on BoDV-2, a conspecific virus of BoDV-1 in the Mammalian 1 orthobornavirus . We synthesized the BoDV-2 nucleoprotein (N) and phosphoprotein (P) according to the reference sequences and evaluated their effects on the RNA polymerase activity of the BoDV-1 large protein (L) and viral replication. In the minireplicon assay, we found that BoDV-2 N significantly enhanced BoDV-1 polymerase activity and that BoDV-2 P supported further enhancement of this activity by N. A single amino acid substitution assay identified serine at position 30 of BoDV-2 N and alanine at position 24 of BoDV-2 P as critical amino acid residues for the enhancement of BoDV-1 polymerase activity. In reverse genetics, on the other hand, BoDV-2 N alone was sufficient to increase the rescue efficiency of the REVec. We showed that the REVec can be rescued directly from transfected 293T cells by using BoDV-2 N as a helper plasmid without cocultivation with Vero cells and following several weeks of passage. In addition, a chimeric REVec harboring the BoDV-2 N produced much higher levels of transgene mRNA and genomic RNA than the wild-type REVec in transduced cells. Our results contribute to not only improvements to the REVec system but also understanding of the molecular regulation of orthobornavirus polymerase activity. Importance Borna disease virus 1 (BoDV-1), a prototype virus of the species Mammalian 1 orthobornavirus , is a nonsegmented negative-strand RNA virus that persists in the host nucleus. The nucleoprotein (N) of BoDV-1 encapsidates genomic and antigenomic viral RNA, playing important roles in viral transcription and replication. In this study, we demonstrated that the N of BoDV-2, another genotype in the species Mammalian 1 orthobornavirus , can participate in the viral ribonucleoprotein complex of BoDV-1 and enhance the activity of BoDV-1 polymerase (L) in both the BoDV-1 minireplicon assay and reverse genetics system. Chimeric recombinant BoDV-1 expressing BoDV-2 N but not BoDV-1 N showed higher transcription and replication levels, whereas the propagation and infectious particle production of the chimeric virus were comparable to those of wild-type BoDV-1, suggesting that the level of viral replication in the nucleus is not directly involved in the progeny virion production of BoDVs. Our results demonstrate a molecular mechanism of bornaviral polymerase activity, which will contribute to further development of vector systems using orthobornaviruses.

Protein kinase C-dependent phosphorylation of Borna disease virus P protein is required for efficient viral spread

2010 ◽  
Vol 155 (5) ◽  
pp. 789-793 ◽  
Author(s):  
Sonja Schmid ◽  
Philippe Metz ◽  
Christine M. A. Prat ◽  
Daniel Gonzalez-Dunia ◽  
Martin Schwemmle
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Disease Virus ◽  
Borna Disease Virus ◽  
Viral Spread ◽  
Kinase C ◽  
P Protein ◽  
Borna Disease

scholarly journals Alpha/Beta Interferon Promotes Transcription and Inhibits Replication of Borna Disease Virus in Persistently Infected Cells

2001 ◽  
Vol 75 (17) ◽  
pp. 8216-8223 ◽  
Author(s):  
Peter Staeheli ◽  
Maria Sentandreu ◽  
Axel Pagenstecher ◽  
Jürgen Hausmann
Keyword(s):  
Disease Virus ◽  
Cultured Cells ◽  
Genome Replication ◽  
Wild Type ◽  
Endogenous Virus ◽  
Viral Mrnas ◽  
Borna Disease Virus ◽  
Persistently Infected ◽  
Alpha Beta ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) is a noncytolytic RNA virus that can replicate in the central nervous system (CNS) of mice. This study shows that BDV multiplication was efficiently blocked in transgenic mice that express mouse alpha-1 interferon (IFN-α1) in astrocytes. To investigate whether endogenous virus-induced IFN might similarly restrict BDV, we usedIFNAR 0/0 mice, which lack a functional alpha/beta IFN (IFN-α/β) receptor. As would be expected if virus-induced IFN were important to control BDV infection, we found that cultured embryo cells of IFNAR 0/0 mice supported viral multiplication, whereas cells from wild-type mice did not. Unexpectedly, however, BDV spread through the CNSs ofIFNAR 0/0 and wild-type mice with similar kinetics, suggesting that activation of endogenous IFN-α/β genes in BDV-infected brains was too weak or occurred too late to be effective. Surprisingly, Northern blot analysis showed that the levels of the most abundant viral mRNAs in the brains of persistently infectedIFNAR 0/0 mice were about 20-fold lower than those in wild-type mice. In contrast, genomic viral RNA was produced in about a 10-fold excess in the brains ofIFNAR 0/0 mice. Human IFN-α2 similarly enhanced transcription and simultaneously repressed replication of the BDV genome in persistently infected Vero cells. Thus, in persistently infected neurons and cultured cells, IFN-α/β appears to freeze the BDV polymerase in the transcriptional mode, resulting in enhanced viral mRNA synthesis and suppressing viral genome replication.

scholarly journals Vaccine-induced protection against Borna disease in wild-type and perforin-deficient mice

2005 ◽  
Vol 86 (2) ◽  
pp. 399-403 ◽  
Author(s):  
Jürgen Hausmann ◽  
Karen Baur ◽  
Karin R. Engelhardt ◽  
Timo Fischer ◽  
Hanns-Joachim Rziha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Neurological Disease ◽  
Cell Epitope ◽  
Wild Type ◽  
Immune Priming ◽  
Boost Immunization ◽  
The Brain ◽  
Deficient Mice ◽  
Borna Disease

Borna disease virus (BDV) can persistently infect the central nervous system and induce CD8+ T-cell-mediated neurological disease in MRL mice. To determine whether specific immune priming would prevent disease, a prime–boost immunization protocol was established in which intramuscular injection of a recombinant parapoxvirus expressing BDV nucleoprotein (BDV-N) was followed by intraperitoneal infection with vaccinia virus expressing BDV-N. Immunized wild-type and perforin-deficient mice remained healthy after intracerebral infection with BDV and contained almost no virus in the brain at 5 weeks post-challenge. Immunization failed to induce resistance against BDV in mice lacking mature CD8+ T cells. Immunization of perforin-deficient mice with a poxvirus vector expressing mutant BDV-N lacking the known CD8+ T-cell epitope did not efficiently block multiplication of BDV in the brain and did not prevent neurological disease, indicating that vaccine-induced immunity to BDV in wild-type and perforin-deficient mice resulted from the action of CD8+ T cells.

Sign in / Sign up

Export Citation Format

Share Document