T cell ignorance in mice to Borna disease virus can be overcome by peripheral expression of the viral nucleoprotein

Hausmann, Jürgen; Hallensleben, Wiebke; Torre, Juan Carlos de la; Pagenstecher, Axel; Zimmermann, Christine; Pircher, Hanspeter; Staeheli, Peter

doi:10.1073/pnas.96.17.9769

Cited by 60 publications

(70 citation statements)

References 45 publications

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“…Thus, these results demonstrate that the kinetics of immune cell priming and virus spread are very important for the two possible outcomes of BDV infection in susceptible MRL mice, i.e., elimination or immunopathology. This notion is underscored by our previous finding that postexposure vaccination of symptomless persistently infected mice cannot clear the infection but rather induces immunopathology (27). Similar conclusions with respect to the delicate balance between protective and immunopathological effects of the antiviral T-cell response were drawn from BDV infection experiments using rats (38).…”

Section: Vol 79 2005 Ifn-␥ Mediates Borna Disease Virus Clearance Fsupporting

confidence: 62%

“…At this early time of infection, the levels of viral spread in the brains of old wild-type and GKO animals were comparable, indicating that BDV initially infected both types of mice but that the virus was later cleared from neurons of wildtype mice but not from those of GKO mice. We previously showed that brain-derived mononuclear cell preparations isolated from wild-type MRL mice infected as newborns contain around 30% CD8 T cells and around 10 to 15% CD4 T cells at the peak of neurological disease (27). We also showed previously that around 30% of the CD8 T cells were TELEISSI specific when labeled with a TELEISSI-H-2K k tetramer directly after isolation (14).…”

Section: Resultsmentioning

confidence: 99%

“…This was indeed the case: all animals in which CD8 T cells were temporarily depleted during the establishment of persistent infection showed persistent infection with a high level of viral spread (Table 1) a MRL wild-type mice were infected with BDV at an age of 100 days and MRL-␤2m 0/0 mice were infected at ages of 90 (nine animals) and 180 (two animals) days. CD8 T cells from wild-type animals were depleted by intravenous administration of the CD8-specific monoclonal rat antibody YTS 169 on days 11 and 15 postinfection as previously described (27). Depletion efficiency was determined by CD4 and CD8 staining and subsequent flow cytometry analyses of peripheral blood leukocytes.…”

Section: Resultsmentioning

confidence: 99%

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

Hausmann¹,

Pagenstecher

Baur³

et al. 2005

J Virol

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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-␥) 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-␥-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-␥-deficient mice but not in wild-type mice. Furthermore, large numbers of eosinophils were present in the inflamed brains of IFN-␥-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-␥ 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-␥ may function as a neuroprotective factor that can limit the loss of neurons in the course of antiviral immune responses in the brain.

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Section: Vol 79 2005 Ifn-␥ Mediates Borna Disease Virus Clearance Fsupporting

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

Hausmann¹,

Pagenstecher

Baur³

et al. 2005

J Virol

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“…Natural infection with BDV occurs in horses, sheep, and other species (21). Although natural BDV infection of mice has not been reported, BDV can replicate in the mouse CNS after intracerebral infection (10,11). However, most mouse strains are resistant to BDV-induced disease, and only mice of few strains, such as MRL, develop neurological disorder following infection with BDV (10,11).…”

mentioning

confidence: 99%

Borna Disease Virus Multiplication in Mouse Organotypic Slice Cultures Is Site-Specifically Inhibited by Gamma Interferon but Not by Interleukin-12

Friedl

Höfer

Auber

et al. 2004

J Virol

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Borna disease virus (BDV) induces a nonpurulent CD4-and CD8-T-cell-dependent meningoencephalitis in susceptible animals. Upon intracerebral infection, BDV replicates in the mouse central nervous system (CNS),but only a few mouse strains develop neurological disorder. The antiviral T cells appear to suppress BDV replication by a noncytolytic mechanism. Since BDV does not replicate in standard mouse cell cultures, the putative role of gamma interferon (IFN-␥) in virus control could not be tested experimentally. Here, we report that mouse organotypic slice cultures can be used to elucidate the complex interactions of BDV, the CNS, and the immune system. We show that BDV replicated in various cell types of mouse cerebellar slice cultures in vitro. In infected slice cultures, a moderate upregulation of the chemokine genes CCL5 and CXCL10 was observed, while expression of various neural genes as well as other chemokine and cytokine genes was not altered. IFN-␥ inhibited the multiplication of BDV in cerebellar and hippocampal slice cultures in a dosedependent manner. However, while complete suppression of BDV was observed in cerebellar slice cultures, inhibition was incomplete in hippocampal slice cultures. Kinetic studies indicated that IFN-␥ protects noninfected cells from infection rather than clearing the virus from infected cells. These results demonstrate that BDV can replicate in cultured neural cells of the mouse if organ integrity is well preserved. They further show that IFN-␥ is a powerful inhibitor of BDV in the absence of blood-borne leukocytes in mouse cerebellar slice cultures.Borna disease virus (BDV) is a nonsegmented, negativestranded RNA virus that can persistently infect the central nervous system (CNS) of a variety of animal species (for a review, see reference 21), which may then develop a severe nonpurulent meningoencephalitis (9,13,17). Natural infection with BDV occurs in horses, sheep, and other species (21). Although natural BDV infection of mice has not been reported, BDV can replicate in the mouse CNS after intracerebral infection (10, 11). However, most mouse strains are resistant to BDV-induced disease, and only mice of few strains, such as MRL, develop neurological disorder following infection with BDV (10, 11). In MRL mice, the antiviral CD8 T cells recognize a single immunodominant epitope located in the BDV nucleoprotein (20). These cells mediate both antiviral protection and neurological disease depending on whether they arrive in the brain before or after BDV has disseminated widely through the organ. Because the antiviral response toward BDV is unaltered in mutant MRL mice lacking perforin or lacking a functional fas system, it appears that the antiviral T cells employ as-yet-undefined, noncytolytic mechanisms to target BDV in infected cells (12). Using knockout and transgenic mice, we showed that alpha interferon (IFN-␣) has the potential to control BDV in the CNS (22). However, the IFN-␣ and IFN-␤ genes are barely expressed in response to BDV infection, indicating that these cyto...

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“…In rodents, BDV-specific CD8 + cytotoxic T lymphocytes (CTL) are mainly directed against the viral nucleoprotein N [17,18]. In mice of the H-2 k haplotype, the N-derived peptide TELEISSI represents the immunodominant CTL epitope [19].…”

Section: Introductionmentioning

confidence: 99%

The functional avidity of virus‐specific CD8⁺ T cells is down‐modulated in Borna disease virus‐induced immunopathology of the central nervous system

et al. 2005

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Borna disease virus (BDV) infection of the central nervous system (CNS) leads to severe neurological symptoms in susceptible MRL mice. The disease is mainly mediated by CD8 + T cells specific for the immunodominant epitope TELEISSI in the BDV nucleoprotein. In this study, TELEISSI/MHC class I tetramers were used to directly visualize antigen-specific CD8 + T cells. We found that on average approximately 30% of the ex vivo analyzed CD8 + T cells in the CNS of diseased mice were specific for TELEISSI. Unexpectedly, the frequency of tetramer-reactive brain-derived CD8 + T cells doubled following overnight culture in the absence of antigen. The majority of CD8 + T cells showed enhanced tetramer binding without up-regulation of T cell receptor surface expression. The frequency of IFN-c-secreting CD8 + T cells after antigen-specific stimulation was higher in overnight cultures than in freshly isolated BDV-specific brain lymphocytes, and enhanced tetramer binding correlated with elevated sensitivity to lower levels of peptide antigen in cytotoxicity assays. These results indicate that the functional avidity of virus-specific CD8 + T cells was down-modulated in vivo. Thus, quantification of tissue-infiltrating CD8 + T cells by the tetramer technique must be interpreted with caution as it may underestimate the real frequency of antigen-specific CD8 + T cells.

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T cell ignorance in mice to Borna disease virus can be overcome by peripheral expression of the viral nucleoprotein

Abstract: ABSTRACT

Cited by 60 publications

References 45 publications

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

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

Borna Disease Virus Multiplication in Mouse Organotypic Slice Cultures Is Site-Specifically Inhibited by Gamma Interferon but Not by Interleukin-12

The functional avidity of virus‐specific CD8⁺ T cells is down‐modulated in Borna disease virus‐induced immunopathology of the central nervous system

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T cell ignorance in mice to Borna disease virus can be overcome by peripheral expression of the viral nucleoprotein

Abstract: ABSTRACT

Cited by 60 publications

References 45 publications

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

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

Borna Disease Virus Multiplication in Mouse Organotypic Slice Cultures Is Site-Specifically Inhibited by Gamma Interferon but Not by Interleukin-12

The functional avidity of virus‐specific CD8+ T cells is down‐modulated in Borna disease virus‐induced immunopathology of the central nervous system

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The functional avidity of virus‐specific CD8⁺ T cells is down‐modulated in Borna disease virus‐induced immunopathology of the central nervous system