Cells usually multiply by duplicating their genome and divide themselves into two daughter cells. Yet, in some organisms, cellular multiplication follows distinct, somewhat bizarre routes. One of these rather unusual ways can be seen in Plasmodium spp., the causative agent of malaria, which remains a major scourge of humanity.
An unusual feature of Plasmodium replication inside erythrocytes, known as schizogony, is the number of nuclei and, hence, daughter cells they produce during one round of intracellular replication. Parasites with odd numbers of nuclei can be readily seen (Fig. 1). Divergence from a geometric expansion, which would lead to 2, 4, 8, 16, or 32 daughter cells, is caused by asynchronous replication.
This suggests that individual nuclei replicate autonomously until a global mechanism takes over and co-ordinates daughter cell formation. This is in striking contrast with nuclear division in other multinucleated cells, such as the early Drosophila embryo, where nuclei follow a geometric expansion, as their division is relatively synchronous.
To gain insight into the regulation of Plasmodium falciparum replication, we conducted a forward genetic screen for the conditional protein expression of protein kinases and identified a kinase as essential for proliferation (Fig. 2)
This kinase is Plasmodium-specific and a crucial regulator of the continuous rounds of DNA replication, histone modification, and regulation of gene expression. We also found that this kinase is required for transmission to the mosquito. This work serves as a starting point to gain a better understanding of Plasmodium replication biology.
We are currently using the human pathogen Plasmodium falciparum to uncover the signalling cascade that orchestrates parasite multiplication in the blood stage of infection. Furthermore, our previous work suggests that a set of unknown genes is involved in parasite replication. We are using classical reverse genetic tools and inducible gene-depletion approaches to characterize the function of these unknown genes. Additionally, we are analyzing the spatiotemporal organization of schizogony using live-cell microscopy.
Our overall aim is to elucidate the regulatory mechanisms that govern Plasmodium replication and understand a process that seemingly cannot be explained by current models of cell cycle regulation.
Currently our interests include:
- Investigating the genes involved in the regulation of replication and nuclear division
- Defining the interactome of the Plasmodium-specific kinase CRK4
- Deciphering the spatiotemporal organization of schizogony
- In collaboration with Zendia GmbH - developing a rapid diagnostics test for Malaria
List of publications
Ganter M, Goldberg JM, Dvorin JD, Paulo JA, King JG, Tripathi AK, Paul AS, Yang J, Coppens I, Jiang RHY, Baker DA, Dinglasan RR, Gygi SP, Duraisingh MT. (2017) Plasmodium falciparum CRK4 directs continuous rounds of DNA replication during schizogony. Nature Microbiology 2: 17017 (DOI: 10.1038/nmicrobiol.2017.17)
Paul AS, Saha S, Jiang RHY, Coleman BI, Kosber AL, Chen C, Ganter M, Espy N, Gubbels MJ, Duraisingh MT. (2015) Parasite calcineurin regulates host cell recognition and attachment by apicomplexans. Cell Host Microbe 18: 49–60 (http://www.cell.com/cell-host-microbe/abstract/S1931-3128(15)00251-6)
Ganter M, Rizopoulos Z, Schuler H, Matuschewski K. (2015) Pivotal and Distinct Role for Plasmodium Actin Capping Protein alpha during Blood Infection of the Malaria Parasite. Molecular Microbiology 96: 84–94 (http://onlinelibrary.wiley.com/doi/10.1111/mmi.12922/full)
Coleman BI, Skillman KM, Jiang RHY, Childs LM, Altenhofen LM, Ganter M, Leung Y, Goldowitz I, Kafsack BFC, Marti M, Llinas M, Buckee CO, Duraisingh MT. (2014) A Plasmodium falciparum Histone Deacetylase Regulates Antigenic Variation and Gametocyte Conversion. Cell Host Microbe 16: 177–186 (http://www.cell.com/cell-host-microbe/abstract/S1931-3128(14)00262-5)
Sattler* J, Ganter* M, Hliscs M, Matuschewski K, Schuler H. (2011) Actin regulation in the malaria parasite. European Journal of Cell Biology 90: 966–971 (http://www.sciencedirect.com/science/article/pii/S017193351000261X)
* Equal contribution
Siden-Kiamos* I, Ganter* M, Kunze A, Hliscs M, Steinbüchel M, Mendoza J, Sinden R, Louis K, Matuschewski K. (2011) Stage-specific depletion of myosin A supports an essential role in motility of malarial ookinetes. Cellular Microbiology 13: 1996-2006 (http://onlinelibrary.wiley.com/doi/10.1111/j.1462-5822.2011.01686.x/full)
* Equal contribution
Ganter M, Schuler H, Matuschewski K. (2009) Vital role for the Plasmodium capping protein (CP) beta subunit in motility of malaria sporozoites. Molecular Microbiology 74: 1356-1367 (http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2958.2009.06828.x/full)
Kursula I, Kursula P, Ganter M, Panjikar S, Matuschewski K, Schuler H. (2008) Structural Basis for Parasite-Specific Functions of the Divergent Profilin of Plasmodium falciparum. Structure 16: 1638-1648 (http://www.sciencedirect.com/science/article/pii/S0969212608003754)
News - Ganter group
Article "The unusual life of malaria parasites"
Article published by our group leaders Markus Ganter & Jude Przyborski (the latter has meanwhile been promoted to Professor at the University Gießen) in the journal "Biologie in unserer Zeit".
How do you manage to control a pathogen that has escaped our immune system for hundreds of thousands of years and is resistant to drugs within a short time? The answer may lie in the unusual biology of the malaria pathogen Plasmodium.
More in issue 03/2018 of "Biologie in unserer Zeit".