CD8 T cells require gamma interferon to clear borna disease virus from the brain and prevent immune system-mediated neuronal damage.
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.
Hausmann
Jürgen
J
Department of Virology, Bavarian Nordic GmbH, Fraunhoferstrasse 13, D-82152 Martinsried, Germany. juergen.hausmann@bavarian-nordic.com
Pagenstecher
Axel
A
Baur
Karen
K
Richter
Kirsten
K
Rziha
Hanns-Joachim
HJ
Staeheli
Peter
P
D000367:Age Factors; D000818:Animals; D001890:Borna Disease / Q000276:immunology* / Q000517:prevention & control* / Q000821:virology; D001891:Borna disease virus / Q000276:immunology* / Q000302:isolation & purification*; D001921:Brain / Q000276:immunology / Q000473:pathology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018925:Chemokines / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D004804:Eosinophils / Q000473:pathology; D005822:Genetic Vectors; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000172:deficiency / Q000276:immunology*; D018793:Interleukin-13 / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009422:Nervous System Diseases / Q000276:immunology* / Q000517:prevention & control* / Q000821:virology; D019590:Nucleocapsid Proteins / Q000096:biosynthesis / Q000235:genetics; D018157:Parapoxvirus / Q000235:genetics; D013154:Spleen / Q000276:immunology; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000008:administration & dosage; D014616:Vaccinia virus / Q000235:genetics; D014765:Viral Vaccines / Q000008:administration & dosage*
D018925:Chemokines; D018793:Interleukin-13; D019590:Nucleocapsid Proteins; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; D007371:Interferon-gamma