The apicoplast as a target for new interventions against malaria: further investigations towards a whole organism vaccination

Abstract

Despite successful efforts to decrease suffering from malaria, the impact on global health still is enormous. Prevention is a key element in the fight against this parasitic disease. Malaria might only be contained and eventually eliminated worldwide by a vaccination that is affordable, safe and efficient. Whole organism vaccinations using antibiotic-attenuated parasites feature these potentials. This study comprises two different aspects. Firstly, the main interest was on peptide-conjugated drugs. A conjugation of drugs with the hepatitis B virus’ large surface antigen (PreS1), which constitutes the virus’ entry key to hepatocytes was tested. Not only could this conjugation be applied in one single shot with the parasites and thus simplify the application process of the vaccine. It could also lead to a specific transport of drugs to the liver and consequently result in reduction in dose and minimisation of adverse side effects. PreS-conjugation with a well-established antimalarial, primaquine, was tested on Plasmodium liver stage parasites. Unfortunately, treatment with the drug conjugation did not show the wished-for effect and therefore needs further investigations. Secondly the mode of action of the new fluoroketolid antibiotic solithromycin regarding the possible usage in a whole organism vaccination was investigated. The compound showed an effect on the apicoplast in blood and liver stage parasites. It could be demonstrated that solithromycin inhibits the inheritance and segregation of this prokaryotic organelle into the parasites’ daughter cells. Experiments with blood stage parasites showed the typical “delayed death” phenomenon. Treated liver stage parasites were arrested in a late stage of development, hence could induce long and various antigen stimulation of the host’s immune system. However, i.v. injection of treated liver stage merosomes in mice revealed that treated daughter cells emerging from the liver are not able to invade erythrocytes. Consequently, there would be no incident of malaria symptoms but only establishment of protection against reinfection. The findings suggest that solithromycin is a suitable drug for attenuation of Plasmodium parasites. Therefore, I promote further investigations e.g. regarding safety, immunostimulation after i.v. merosome injection and subsequently challenging with viable parasites for a further development of whole organism vaccinations against malaria.