Beeinflussung des Verlaufs von Pneumokokken-Meningitis in Mäusen durch Stimulation mit einem Cytosin-Guanin-haltigen Oligonukleotid
The Impact of stimulation with an oligonucleotide containing cytosin and guanin on the course of pneumococcal meningitis in mice
von Laura Zacke
Datum der mündl. Prüfung:2020-02-04
Erschienen:2020-01-28
Betreuer:Prof. Dr. Roland Nau
Gutachter:PD Dr. Fred Lühder
Gutachter:Prof. Dr. Holger Reichardt
Dateien
Name:Dissertation Laura Zacke.pdf
Size:2.63Mb
Format:PDF
Zusammenfassung
Englisch
Streptococcus pneumoniae is the most common cause of bacterial meningitis in small children, the elderly and in immunocompromised patients. The aim of this study was therefore, to test if a single intraperitoneal injection of CpG can stimulate the immune system to such a level as to be able to allow the host to overcome pneumococcal meningitis. Three days prior to the infection with S. pneumoniae D39 an intraperitoneal injection with either 100µg CpG or buffer was given to immunocompetent, neutropenic and TLR9-deficient mice. Neutropenia was achieved by applying anti-Ly6G monoclonal antibodies in some of the mice for one week, starting four days before infection. After the infection with S. pneumoniae D39 the mice were monitored for the duration of 14 days and Kaplan-Meier survival analyses were performed. A single administration of CpG significantly improved survival time of neutropenic mice, with the survival rate being three times higher than in mice treated with buffer. In addition, symptoms of disease occurred later and were less severe than in buffer treated mice. Similar results were observed in immunocompetent mice with the survival rate being twice as high as the buffer treated mice. There was no difference between the TLR9-deficient mice, confirming that the effect of CpG is TLR9-dependent. Increasing the CpG dosage up to 200µg led to 100% mortality after 88 hours. We also analysed the bacterial burden and level of IL-12/IL-23p40, MIP-1α and IFN-γ in the spleen, cerebellum, blood and serum 24 and 36 hours following infection. Bacterial burden in blood was significantly higher in buffer treated neutropenic and immunocompetent mice compared to CpG treated mice. Bacterial burden was also high in the spleen and cerebellum of buffer treated mice but only the difference in the neutropenic mice was statistically significant. Our results showed a correlation between high IL-12/IL-23p40- and MIP-1α-levels and a lower bacterial burden in CpG treated neutropenic mice. As the neutropenic mice are lacking CD11b+Ly-6G+Ly-6Cint neutrophils, these results suggest that microglia play an important role in overcoming pneumococcal meningitis and can be stimulated by CpG
Keywords: CpG; pneumococcal meningitis