Die Rolle der Wirtszellproteine für das Überleben und die Vermehrung des menschlichen Malaria-Parasiten P. falciparum
Zellbiologie
Zusammenfassung der Projektergebnisse
This project aimed to answer the question as to whether the malaria parasite P. falciparum uses human protein present within the red blood cell for its own purposes. Our preliminary results suggested that parasite growth can be affected by inactivating the function of a specific family of proteins, referred to as HSP70. We therefore designed a number of experiments to further test and elaborate on our hypothesis. Unfortunately, many of these experiments relied on a specific reagent which was suddenly withdrawn from the market shortly after this project was financed. Despite attempts to find alternatives, we were thus unable to proceed with our original research plan. As a fall-back, we used an alternative experimental system involving sequestering recombinant protein into re-sealed host cells and monitoring parasite growth and host cell modification. Despite a concerted effort to standardise protocols, reagents and methods, this strategy did not produce high-quality results which statistically supported the experimental hypothesis. Serendipity provided us with a further alternative method to experimentally interrogate our hypothesis. Using reverse genetics paired with protein biochemistry we were finally able to provide strong support that the parasite relies on human HSP70 for one specific process: the generation of raised structures on the surface of the host cell. These structures are essential for effective presentation of another parasite protein, PfEMP1. Although this protein is not essential for parasite growth in cell culture, it is the major parasite virulence factor and involved in antigenic variation and thus avoidance of immune surveillance when in human patients. We think it likely that parasites lacking correctly presented PfEMP1 will be rapidly cleared within human patients. This also implies that the correct interaction of an exported parasite protein (PFA66) and human HSP70 could represent an attractive target for drug development, especially considering the novelty of the interaction. This project was (amongst other things) designed to elucidate the role of human HSP70 in protein traffic from the parasite to the host cell. However, our data instead support a far more important role of this protein in parasite virulence characteristics. https://www.faz.net/aktuell/rhein-main/neue-forschung-im-kampf-gegen-malaria-17613610.html
Projektbezogene Publikationen (Auswahl)
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(2021) Co-chaperone involvement in Knob biogenesis implicates host-derived chaperones in malaria virulence. PLOS Pathogens 17(10): e1009969
Diehl M, Roling L, Rohland L, Weber S, Cyrclaff M, Sanchez CP, Beretta CA, Simon CS, Guizetti J, Hahn J, Schulz N, Mayer MP, Przyborski JM
