Skip to main content

Adding Pieces to the Puzzle of Sexual Differentiation In P. falciparum: A Systematic Analysis of RNA Processing

Periodic Reporting for period 1 - SPARk (Adding Pieces to the Puzzle of Sexual Differentiation In P. falciparum: A Systematic Analysis of RNA Processing)

Reporting period: 2016-04-01 to 2018-03-31

Malaria remains one of the most devastating diseases in modern times, with the heaviest mortality concentrated in young children living in resource-poor environments. Plasmodium falciparum causes the most severe form of malaria. The parasites have a complex life cycle, switching between a host and a mosquito vector. Transformation of a subset of parasites into specialized stages capable of sexual development – the gametocytes – is one of the most astonishing, yet not well understood, Plasmodium life cycle phases. As preparatory work for this proposal during my time at Harvard School of Public Health, I identified pathways specifically upregulated at the onset of sexual differentiation, an important gap in our knowledge of gametocytogenesis. Among these, four genes involved in different aspects of post-transcriptional gene regulation were highly upregulated. Studying this aspect of gametocyte biology can add to our understanding of how Plasmodium parasites orchestrate complex genetics switches and modulate the cellular response to developmental signals.
The aim of this proposal is to provide insight how these RNA-binding proteins contribute to sexual stage-specific gene expression. This project employs genetic approaches to investigate the role of these proteins during sexual development of P. falciparum. For that I will generate transgenic parasites and analyse the resulting phenotype in detail. Additionally, this study aims at characterisation the splicing activity of recombinantly produced proteins and to determine target RNAs in order to elucidate the underlying mechanism of RNA processing control.
This proposal can contribute to improved health conditions in malaria-endemic countries through a better understanding of malaria transmission and new approaches to treat the disease. Completion of the scientific project in combination with the proposed structured acquisition of professional skills will enable me to reintegrate into the European research community.
The research activity conducted during the project “SPARk: Adding Pieces to the Puzzle of Sexual Differentiation in P. falciparum: A Systematic Analysis of RNA Processing” mainly focused on reverse genetics in Plasmodium falciparum. During the funding period clonal transgenic parasite lines for the proposed four genes could be generated. All genes had predicted functions in controlling gene expression. Two transgenic parasite lines appear to have an important phenotype with the overall number of gametocytes reduced. For dissemination of the findings to the scientific community a manuscript regarding the results obtained in this project is in preparation. Regarding the exploitation of the obtained results, it is important to note that there is an urgent need for target-based drug development directed against P. falciparum gametocytes. If I can describe genes with a validated importance for Plasmodium gametocyte development, this would lay the basis for future drug development efforts.
Another important aspect of the SPARk project was to provide continuous professional development for myself; thus enabling the acquisition of an independent research position. I successfully finished a course focusing on continuous professional training, especially designed for young researchers. The hessian Centre for Didactics (Giessen, Germany) offers the certified course ‘Competencies for Professional Teaching’. This programme targets the structured development of teaching and leadership competencies over the course of 2-3 years by covering a wide range of fields such as teaching, preparing exams, managing conflicts, and providing equal opportunities. Additionally, I supervised four Master and three Bachelor students thus far, helping me prepare for the multi-faceted roles of supervisor, mentor, and project manager. Recently, I was able to attain a leading independent research position, as group leader within the LOEWE Center ‘DRUID: Novel Drug Targets against Poverty-Related and Neglected Tropical Infectious Diseases’.
The goal of global malaria eradication will be unachievable without the development of a new generation of tools focused on interrupting malaria transmission. The project SPARk helped to lay the basis for the development of new tools by providing validated targets against P. falciparum gametocytes. Thus, the study is likely to have a positive impact on the health and well-being of all, especially because it can improve problems that afflict humanity’s most vulnerable: the spread of diseases in the developing world and poverty. The impact of this project is expanding the frontiers of scientific knowledge and helping fight the diseases of the poor.
Dr. Buchholz receives the Rudolphi Medal (German Society for Parasitology) for excellent researcher