Integrative analysis of nuclear division mechanisms in malaria parasite

• Applicant: Dr. Julien Guizetti
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Cell Biology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 349355339

Plasmodium falciparum causes the most severe form of malaria killing about half a million children every year. Pathogenesis and clinical symptoms are linked to asexual proliferation in red blood cells and severity of malaria infection is predicted by parasite load. Even though mitosis is fundamental to the rapid proliferation of this eukaryotic pathogen the mechanisms of nuclear division are poorly studied and thus presents an exciting new avenue for research. P. falciparum mitosis displays significant morphological differences when compared to any model organism suggesting that non-canonical division mechanisms are in place. By combining recent advances in live cell imaging, super-resolution microscopy, and genome-editing technologies I aim to uncover the molecular and cellular events that govern those mechanisms.Mitosis is a highly dynamic process that requires precise coordination of multiple structural elements. Currently, it is unclear how chromosome replication and segregation are coordinated. Further, a lack of canonical cell division checkpoints has been suggested and Plasmodial centrosomes contain specific centrins of unknown function. Hence, the three main objectives of my proposal are: i) Analyze coordination of chromosome replication, attachment and segregation using live cell imaging. ii) Quantify whether apparent lack of mitotic checkpoints causes frequent segregation errors using novel DNA live cell markers and super-resolution microscopy. iii) Functionally investigate the peculiar dynamics, and morphology of centrosomes using genome-editing and correlative light and electron microscopy. These novel approaches represent a significant departure from mainstream malaria research and will drastically improve our understanding of cell division in this major eukaryotic pathogen. Newly described molecular markers may enable high-content screening and lead to new intervention strategies against malaria.

• DFG Programme: Research Grants