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Profilin in Plasmodium berghei gliding motility and development

Moreau, Catherine A.

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Profilin is an actin binding protein playing a central role in cell motility. Interestingly, the group of Apicomplexa that contains a number of important pathogens like Toxoplasma and Plasmodium has a very unusual type of profilin. In these parasites, profilin contains three additional structural motifs that are not found in other organisms like yeast, plants or animals. Additionally, apicomplexan parasites have a unique way of cell locomotion that is based on an unusual actin-myosin motor. This motor enables the invasive stage of the parasite to move with high speeds. In Plasmodium the sporozoite, the stage transmitted to the skin of the host by a mosquito, displays the highest speed. One of the additional structural motifs of apicomplexan profilin, a β-hairpin extension called the arm motif, has been suggested to be involved in actin binding. During this work, I could show through a combination of biochemical and computational analyses of proteins, molecular genetics of Plasmodium berghei parasites and biophysical measurements on sporozoites that this assumption is true. Not only could we show that the arm motif is involved in actin binding, but we could show that the arm motif is crucial for 2D gliding motility of sporozoites. Deletion of the arm motif produced sporozoites that were less virulent than wild type sporozoites. Certain mice were able to survive and clear sporozoites-induced infections with the arm deletion parasites and were later protected against severe malaria and able to clear wild type infections. This indicates, that it should in principle be possible to generate a genetically attenuated parasite for use in sporozoite-induced blood stage vaccinations. We found indications that another additional motif, the acidic loop, is involved in defining the arm motif orientation and thus influences actin binding. Even though profilin was suggested to be essential I was able to generate a profilin knockout. This revealed that profilin is not essential in the blood stage, although the growth rate of the profilin knockout was significantly reduced. However, profilin was necessary during mosquito development, as loss of profilin led to impaired crystalloid body integrity and most significantly, a lack of salivary gland sporozoites.

Item Type: Dissertation
Supervisor: Frischknecht, Prof. Dr. Friedrich
Date of thesis defense: 22 September 2017
Date Deposited: 15 Jan 2019 13:22
Date: 2019
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
570 Life sciences
Controlled Keywords: Plasmodium, Parasit, Protozoen
Uncontrolled Keywords: Actin-Myosin Motor
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