High-Dose Borna Disease Virus Infection Induces a Nucleoprotein-Specific Cytotoxic T-Lymphocyte Response and Prevention of Immunopathology

ABSTRACT Experimental Borna disease virus (BDV) infection of rats and natural infection of horses and sheep leads to severe central nervous system disease based on immunopathological pathways. The virus replicates slowly, and the cellular immune response results in immunopathology. CD8+ T cells exert effector cell functions, and their activity results in the destruction of virus-infected cells. Previously, Oldach and colleagues (D. Oldach, M. C. Zink, J. M. Pyper, S. Herzog, R. Rott, O. Narayan, and J. E. Clements, Virology 206:426–434, 1995) have reported protection against Borna disease after inoculation of high-dose cell-adapted BDV. Here we show that the outcome of the infection, i.e., immunopathology versus protection, is simply dependent on the amount of virus used for infection. High-dose BDV (106 FFU) triggers an early virus-specific reaction of the immune system, as demonstrated by strong cellular and humoral responses. In particular, the early presence and function of nucleoprotein-specific CD8+ T cells could be demonstrated in the brain. We present evidence that in a noncytolytic and usually persistent virus infection, high-dose input virus mediates early control of the pathogen due to an efficient induction of an antiviral immune mechanism. From these data, we conclude that immune reactivity, in particular the cytotoxic T-cell response, determines whether the virus is controlled with prevention of the ensuing immunopathological disease or whether a persistent infection is established.

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Mechanisms of suppression of cytotoxic T-cell responses in murine lymphocytic choriomeningitis virus infection.

Journal of Experimental Medicine ◽

10.1084/jem.145.5.1131 ◽

1977 ◽

Vol 145 (5) ◽

pp. 1131-1143 ◽

Cited By ~ 24

Author(s):

M B Dunlop ◽

R V Blanden

Keyword(s):

T Cells ◽

T Cell ◽

Virus Infection ◽

Lymphocytic Choriomeningitis ◽

T Cell Response ◽

Cytotoxic T Cell ◽

Lymphoid Tissues ◽

High Dose ◽

High Level

The cytotoxic T-cell response to lymphocytic choriomeningitis (LCM) virus infection was suppressed either in vitro or in vivo by addition of a high level of syngeneic virus-infected cells or syngeneic cells from congenital LCM virus carriers to the environment of the responding cells. This effect was not duplicated by formaldehyde-fixed carrier cells, nor could it be accounted for by 'cold' target competition by carrier cells at the level of the cytotoxicity assay. Conversely, suppression was produced in vivo by water-lysed, ultrasonically treated carrier cell suspensions, or by a large dose of LCM virus equivalent to that contained in the carrier cells. Thus a high level of infectious virus was a common factor in all observed examples of suppression. Based upon this, the following hypothesis, a form of 'forbidden clone deletion,' was proposed to account for virus-specific cytotoxic T-cell tolerance in LCM virus congenital carriers, or in high dose suppression. A high level of virus in lymphoid tissues, while not cytopathic per se, may result in infection of all or most T cells; this then may lead to deletion either via 'suicide' of individual, infected, cytotoxic T cells with receptors specific for virus-induced antigenic patterns on their own surface membranes, or by mutual lysis of two adjacent T cells.

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Prevention of Virus Persistence and Protection against Immunopathology after Borna Disease Virus Infection of the Brain by a Novel Orf Virus Recombinant

Journal of Virology ◽

10.1128/jvi.79.1.314-325.2005 ◽

2005 ◽

Vol 79 (1) ◽

pp. 314-325 ◽

Cited By ~ 38

Author(s):

Marco Henkel ◽

Oliver Planz ◽

Timo Fischer ◽

Lothar Stitz ◽

Hanns-Joachim Rziha

Keyword(s):

T Cells ◽

Virus Infection ◽

Disease Virus ◽

Neuronal Damage ◽

Orf Virus ◽

Vector System ◽

Necrosis Factor Alpha ◽

Borna Disease Virus ◽

The Brain ◽

Borna Disease

ABSTRACT The Parapoxvirus Orf virus represents a promising candidate for novel vector vaccines due to its immune modulating properties even in nonpermissive hosts such as mouse or rat. The highly attenuated Orf virus strain D1701 was used to generate a recombinant virus (D1701-VrVp40) expressing nucleoprotein p40 of Borna disease virus, which represents a major antigen for the induction of a Borna disease virus-specific humoral and cellular immune response. Infection with Borna disease virus leads to distinct neurological symptoms mediated by the invasion of activated specific CD8+ T cells into the infected brain. Usually, Borna disease virus is not cleared from the brain but rather persists in neural cells. In the present study we show for the first time that intramuscular application of the D1701-VrVp40 recombinant protected rats against Borna disease, and importantly, virus clearance from the infected brain was demonstrated in immunized animals. Even 4 and 8 months after the last immunization, all immunized animals were still protected against the disease. Initial characterization of the immune cells attracted to the infected brain areas suggested that D1701-VrVp40 mediated induction of B cells and antibody-producing plasma cells as well as T cells. These findings suggest the induction of various defense mechanisms against Borna disease virus. First studies on the role of antiviral cytokines indicated that D1701-VrVp40 immunization did not lead to an enhanced early response of gamma or alpha interferon or tumor necrosis factor alpha. Collectively, this study describes the potential of the Orf virus vector system in mediating long-lasting, protective antiviral immunity and eliminating this persistent virus infection without provoking massive neuronal damage.

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Intracerebral Borna Disease Virus Infection of Bank Voles Leading to Peripheral Spread and Reverse Transcription of Viral RNA

PLoS ONE ◽

10.1371/journal.pone.0023622 ◽

2011 ◽

Vol 6 (8) ◽

pp. e23622 ◽

Cited By ~ 14

Author(s):

Paula Maria Kinnunen ◽

Hanna Inkeroinen ◽

Mette Ilander ◽

Eva Riikka Kallio ◽

Henna Pauliina Heikkilä ◽

...

Keyword(s):

Virus Infection ◽

Disease Virus ◽

Reverse Transcription ◽

Viral Rna ◽

Borna Disease Virus ◽

Bank Voles ◽

Borna Disease

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Borna disease virus infection in Italian children. A potential risk for the developing brain?

Apmis ◽

10.1111/j.1600-0463.2008.00m12.x ◽

2008 ◽

Vol 116 ◽

pp. 70-73 ◽

Cited By ~ 6

Author(s):

ANNA-MARIA PATTI ◽

ANTONELLA VULCANO ◽

ELISA CANDELORI ◽

RENATO DONFRANCESCO ◽

HANNS LUDWIG ◽

...

Keyword(s):

Virus Infection ◽

Disease Virus ◽

Potential Risk ◽

Developing Brain ◽

Borna Disease Virus ◽

Italian Children ◽

Borna Disease

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Persistent Borna disease virus infection of neonatal rats causes brain regional changes of mRNAs for cytokines, cytokine receptor components and neuropeptides

Brain Research Bulletin ◽

10.1016/s0361-9230(99)00081-7 ◽

1999 ◽

Vol 49 (6) ◽

pp. 441-451 ◽

Cited By ~ 41

Author(s):

Carlos R Plata-Salamán ◽

Sergey E Ilyin ◽

Dave Gayle ◽

Anna Romanovitch ◽

Kathryn M Carbone

Keyword(s):

Virus Infection ◽

Disease Virus ◽

Cytokine Receptor ◽

Neonatal Rats ◽

Borna Disease Virus ◽

Borna Disease

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Higher prevalence of Borna disease virus infection in blood donors living near thoroughbred horse farms

Journal of Medical Virology ◽

10.1002/(sici)1096-9071(199707)52:3<330::aid-jmv16>3.0.co;2-m ◽

1997 ◽

Vol 52 (3) ◽

pp. 330-335 ◽

Cited By ~ 33

Author(s):

Hirokazu Takahashi ◽

Takaaki Nakaya ◽

Yurie Nakamura ◽

Sayumi Asahi ◽

Yoshiko Onishi ◽

...

Keyword(s):

Virus Infection ◽

Disease Virus ◽

Blood Donors ◽

Borna Disease Virus ◽

Thoroughbred Horse ◽

Horse Farms ◽

Borna Disease

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

Journal of Virology ◽

10.1128/jvi.75.21.10460-10466.2001 ◽

2001 ◽

Vol 75 (21) ◽

pp. 10460-10466 ◽

Cited By ~ 16

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.

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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

Journal of Virology ◽

10.1128/jvi.79.21.13509-13518.2005 ◽

2005 ◽

Vol 79 (21) ◽

pp. 13509-13518 ◽

Cited By ~ 31

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.

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