Publikationsserver der RWTH Aachen University
Immunpathologische Folgen von Infektionen des ZNS durch das lymphotrope Maus-Herpesvirus 68 als Modell für Epstein-Barr-Virus assoziierte ZNS-Erkrankungen des Menschen
Abstract
dc:descriptionThe murine herpesvirus 68 (MHV-68) is a gamma-herpesvirus and closely related to the Epstein-Barr virus (EBV). After the infection of mice with MHV-68, a mononucleosis-like phase ensues with splenomegalie. The murine B-lymphocytes are infected latent and involved in the dispersion of the virus through the body. Macrophages and dendritic cells are also infected, and could infect other cells and organs with MHV-68. With the animal model MHV-68/mice, it is possible to map the exact infection route of MHV-68 and develop therapy options. The achieved results could be transferred to EBV infection. Many similarites have been established between MHV-68 and EBV. The transactivator G50/Rta from MHV-68 is closely related to BRLF1/Rta from EBV. G50/Rta is necessary for the establishment of latency but also for the reactivation of the lytic cycle. BRLF1/Rta from EBV cannot fulfil this function alone as the product of the BZLF1-gene is also necessary. There is no homologous BZLF1 gene product known for MHV-68. An important part of this dissertation was to map the regulation of the G50/Rta-promoter. The regulation of the BRLF1/Rta-promoter is widely known. If the regulation of the G50/Rta conforms to the regulation of the BRLF1/Rta-promoter, then a further shared aspect can be established between MHV-68 and EBV infection. The main focus of this dissertation was the analysis of gamma-herpesvirus-associated neurological diseases in view of a possible therapy. Therefore, the G50-promoter from MHV-68 was analysed. Regulatory sequence motifs were identified in the domains 66141-66250, 66251-66534 and 66397-66534; they are important for the induction and repression of the G50-promoter in reaction to the stimuli TPA, anti-IgM and super-infection with MHV-68. With the help of the Yeast One Hybrid system, the heat shock protein 70 kDa (Hsp70kDa) could be recognized as a binding partner for the G50-promoter. The actual transcription start point of the G50-gene lays 8bp before the ATG. To detect the precise infection date of the brain of MHV-68 infected mice, the kinetics of the infection with MHV-68 was explored. Viral DNA in the CNS could be measured 3 days after infection, and an apparent infection could be detected 6 days after infection. The virus was persistent for months. Massive infiltrates of CD3 positive lymphocytes in the CNS appeared 9 days after infection and were particularly found in animals with very high viral load. The virus detected in CNS was active. To identify the cells which spread the virus through the body of the mice, B- and T-cell deficient mice were infected with MHV-68. After infection of B- and T-cell deficient mice, an infection of the CNS could also be detected. This leads to the conclusion that B- and T-cells are not necessary for the infection of the brain. The immune competent mice had a lower viral load than the immune deficient mice indicating that B- and T-cells are necessary for the control of MHV-68 infection. Long term consequences could not be detected in the CNS of BALB/c-mice, which were infected with MHV-68 for 6 months. The brain structure looked normal. Infiltrates could also not be detected. Therapy options were first tested in vitro in a MHV-68 positive cell line, LymphoMHV-68. The tested drugs were also analysed for their effect on MHV-68 activity. Everolimus inhibited the proliferation but enhanced the virus activity. Cyclosporine A also inhibited proliferation but did not have an effect on the virus activity. Aspirin inhibited proliferation at a concentration of 20mM completely but did not have an effect on virus activity. Methylprednisolone neither had an effect on the proliferation nor on the virus activity. A further question was: can the generation of autoantibodies induce the tissue damage? In some MHV-68 high positive tissues, necrosis was found. In MHV-68 positive animals, autoantibodies were found which could induce the tissue damage of MHV-68 infected mice. The regulation of the G50-promoter was rudimentarily analysed and drugs were selected for testing in vivo.
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2008
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Kolbe, Sabrina Cäcilie
- Contributors dc:contributor
-
- Ritter, Klaus
Subjects
dc:subject × 12Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- ger