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Published on: July 24, 2016
CD8 T cells require gamma interferon to clear borna disease virus from the brain and prevent immune system-mediated
Jürgen Hausmann1, Axel Pagenstecher, Karen Baur
1Department of Virology, Bavarian Nordic GmbH, Fraunhoferstrasse 13, D-82152 Martinsried, Germany. juergen.hausmann@bavarian-nordic.com
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-gamma) 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-gamma-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-gamma-deficient mice but not in wild-type mice. Furthermore, large numbers of eosinophils were present in the inflamed brains of IFN-gamma-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-gamma 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-gamma may function as a neuroprotective factor that can limit the loss of neurons in the course of antiviral immune responses in the brain.
Insights
Gamma interferon (IFN-gamma) is crucial for clearing Borna disease virus (BDV) from the brain and protecting neurons. This cytokine is essential for MRL mice to resist BDV infection and prevent neurological damage.
Area of Science:
- Neurovirology
- Immunology
- Central Nervous System (CNS) Infections
Background:
- Borna disease virus (BDV) causes fatal meningoencephalitis in young MRL mice, mediated by H-2(k)-restricted CD8 T cells targeting the viral nucleoprotein N.
- Persistent BDV infection is not cleared spontaneously in MRL mice.
- Gamma interferon (IFN-gamma) is investigated for its role in BDV infection resistance and clearance.
Purpose of the Study:
- To investigate the role of gamma interferon (IFN-gamma) in host resistance and viral clearance during Borna disease virus (BDV) infection in MRL mice.
- To determine the neuroprotective effects of IFN-gamma in the context of BDV-induced central nervous system (CNS) disease.
Main Methods:
- Comparison of BDV infection outcomes in wild-type MRL mice versus MRL mice genetically deficient in IFN-gamma.
- Assessment of viral clearance, neuronal damage, and immune cell infiltration (including CD8 T cells and eosinophils) in the brains of infected mice.
- Evaluation of N-specific vaccination efficacy in protecting against persistent BDV infection in different MRL mouse models.
Main Results:
- IFN-gamma-deficient MRL mice (young and old) were highly susceptible to BDV infection, exhibiting severe hippocampal neuron damage.
- Wild-type MRL mice showed resistance and eventual clearance of BDV from neurons, with IFN-gamma playing a central role.
- IFN-gamma-deficient mice displayed increased eosinophil infiltration in the brain, linked to elevated interleukin-13 and chemokines CCL1/CCL11.
Conclusions:
- IFN-gamma is essential for host resistance against CNS infection with BDV and for clearing the virus from neurons.
- IFN-gamma acts as a critical neuroprotective factor, limiting neuronal loss during antiviral immune responses in the brain.
- Age-dependent resistance in old MRL mice to BDV is CD8 T cell-dependent, highlighting complex immune mechanisms in controlling viral encephalitis.
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