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Tim Gilberger

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Cell Biology of Human Parasites

"The multi-disciplinary structure of the CSSB offers a unique platform for the understanding of complex diseases such as malaria. It fosters the integration of cell biological objectives into an infrastructure that is powered by high resolution imaging, structural elucidation and systems biology."

Tim Gilberger, CSSB Group Leader

Previous and current research

Red Blood Cell Invasion of the Malaria Parasite
One of the most significant steps in the complex life cycle of the malaria parasite is the invasion of human erythrocytes. All clinical symptoms are connected with the modification and destruction of the host cell. The Gilberger group studies the molecular basis for erythrocyte invasion by combining genetic, cellular, biochemical, structural and systems biology based approaches with the aim to deliver a detailed molecular blueprint that will help define novel therapeutic targets.

Adhesive and Regulatory Elements
To survive and multiply the malaria parasite invades red blood cells in less than a minute. The physical link between the parasite and erythrocyte membrane is generated by the interaction of parasite proteins that bind with their adhesive, extracellular domain to specific surface structures of the erythrocyte. This physical bridge between parasite and its host cell is linked to the actin-myosin motor of the parasite powering the invasion.

One cellular control mechanism is the post-translational modification of proteins due to phosphorylation. We are investigating kinase dependent phosphorylation of cytoplasmic domains of type I invasins as a switch mechanism in the molecular cascade triggering and powering the invasion process of human red blood cells. We are interested in the identification of the responsible kinases as well as in the dissection of signaling and effector pathways mediated by the cytoplasmic domain of selected invasins.

Structural elements
The motor complex is anchored in the membranes of the inner membrane complex (IMC) and is located under the plasma membrane in the malaria parasite. The obvious fundamental role of the IMC stands in contrast to our rudimentary knowledge of its components, dynamics and biogenesis in the malaria parasite. We explored a systems biological approach and subsequent phylogenetic profiling to identify novel IMC proteins. We revealed high levels of diversity in terms of structural organization and phylogenetic trajectories of Plasmodium IMC proteins, which exemplify the adaptive molecular composition of this structure. Using high resolution and time-lapse microscopy we investigated i) the dynamic of this structure during parasite maturation, ii) its role in pre-sexual differentiation and iii) its sub-compartmentalization.

Global networks
Erythrocyte invasion is the result of the interplay of a complex protein network. The Bozdech laboratory (NTU, Singapore) constructed a high confidence gene interactome network using a probabilistic Bayesian network approach. Using the assembled interactome network, we identified a sub-network of proteins that are associated with merozoite invasion by retrieving 418 predicted proteins directly linked to previously established invasion associated proteins. Using a GFP-tagging approach, we selected 70 proteins for experimental analysis of their predicted association with invasion. 42 proteins could be localized in the parasite, of which 31 were targeted either to the apical organelles, the parasite surface or the IMC, compartments directly linked to the invasion process. Using reverse genetics, cell biological and biochemical approaches we are now studying the function of selected individual proteins in the invadome.

Future Goals
By understanding the molecular mechanism of host cell invasion at the highest possible resolution, we hope to provide a solid basis for the development of novel, anti-malarial strategies that will target this crucial process.

Selected publications
Kono M, et al. (2016) Pellicle formation in the malaria parasite. J Cell Sci; 129: 673-80.

Paul AS, et al. (2015) Parasite Calcineurin Regulates Host Cell Recognition and Attachment by Apicomplexans. Cell Host Microbe; 18: 49-60.

Kono M, et al. (2012) Evolution and architecture of the inner membrane complex in asexual and sexual stages of the malaria parasite. Mol Biol Evol; 29: 2113-32.

Grüring C, et al. (2011) Development and host cell modifications of Plasmodium falciparum blood stages in four dimensions. Nature Commun; 2: 165.

Hu G, et al. (2010) Transcriptional profiling of growth perturbations of the human malaria parasite Plasmodium falciparum. Nature Biotechnol; 28: 91-8.



Picture: © Marta Mayer
Drucker