Research area A

NUTRIENT UPTAKE AND METABOLISM

During the pathogenic blood phase of the complex life cycle Plasmodium spends >99.9% of its life cycle inside host cells. This obligate intracellular niche in an extreme environment (i.e. terminally differentiated erythrocytes) requires metabolic adaptations, which until to date form the basis for antimalarial chemotherapy. This is exemplified by the drug chloroquine that inhibits non-toxic (hostderived) hemoglobin degradation in the parasite food vacuole. In this research area four projects examine the strict dependence of the parasite on external nutrient supply, ranging from ions to complex lipids.


Projects


Project A1 - 1st Cohort

Conserved and Lineage-specific Functions of Plasmodium Membrane Transport Proteins

KAI MATUSCHEWSKI (HUB) in partnership with Alexander Maier (ANU), Kiaran Kirk (ANU), and Giel van Dooren (ANU) 

In this project a systematic experimental genetics analysis of candidate membrane transport proteins that are shared amongst apicomplexan parasites or unique to distinct Plasmodium species will identify and prioritize candidate drug targets. Lipids are often overlooked as some of the most important and versatile principal cellular components.

Francois Korbmacher


Project A2 - 1st Cohort

Plasmodium falciparum lipid metabolism as a target for malaria intervention strategies

ALEXANDER MAIER (ANU) in partnership with Edda Klipp (HUB)

The project will combine state-of-the-art lipidomics analyses of synchronized and selected parasite stages with mathematical modelling of lipid fluxes in order to select key enzymes and transporters that can be validated experimentally. An integrated mathematical model for ion and cell volume homeostasis in the malaria parasite-infected human erythrocyte remains elusive.

Merryn Fraser


Project A3 - 1st Cohort

An integrated thermodynamic model of ion homeostasis in the malaria parasite

EDDA KLIPP (HUB) in partnership with KIARAN KIRK (ANU) and Adele Lehane (ANU)

The project entails obtaining quantitative biochemical and physiological data and incorporating these into a quantitative description of ion homeostasis in the intracellular malaria parasit.  The model will contribute to an understanding of the mechanism-of-action of ‘ion-disrupting’ antimalarials that are emerging as priority drug candidates in the malaria-medicine pipeline.

Jorin Diemer, Maxim Karnetzski


Project A4 - 1st Cohort 

Cyclic nucleotide-mediated ion homeostasis in the malaria parasite

NISHITH GUPTA (HUB) in partnership with Kiaran Kirk (ANU) and Alexander Maier (ANU)

The project will employ ultra-fast optogenetic regulation of ion channels to monitor the immediate cellular responses upon external stimuli and identify potential novel regulatory cascades that are unique to parasite stage conversion.

Theresa Störiko


Project A1 - 2nd Cohort

Conserved and Lineage-specific Functions of Plasmodium Membrane Transport Proteins

KAI MATUSCHEWSKI (HUB) in partnership with Alexander Maier (ANU)

An intracellular life style and population expansion strictly depends on efficient uptake of ions, nutrients, building blocks and membrane lipids. Mammalian Plasmodium parasites have very tight host species barriers and co-evolved with their respective hosts. Work in two Plasmodium parasite models, the murine malaria model P. berghei and P. falciparum blood cultures, combines phenotyping of the entire parasite life cycle and parasite/host cross-talk during infection with in-depth analysis of blood infection by the human human pathogen. These studies are expected to uncover druggable targets and generate virulence attenuated parasite lines for preclinical testing of malaria vaccine strategies.

Frederick Hupperz

 


Project A2 - 2nd Cohort

Lipids as targets for antimalarial drugs

ALEXANDER MAIER (ANU) in partnership with Edda Klipp (HUB), Melanie Rug (ANU), and Martin Blume (RKI)

Lipids – together with proteins and nucleid acids – are the major building blocks of cells. We have recently determined the lipid composition of the different life cycle stages of Plasmodium falciparum and Plasmodium berghei. Based on this data we will now determine key molecules that are important for lipid import and metabolism and explore their role and potential as drug targets. A bioinformatic overview obtained in silico will guide us to identify rate limiting steps in the lipid metabolism. These predictions will be verified using transgenic approaches using CRISPR/Cas9 and various tagging strategies. Our approaches will also determine the localization, function and importance of these enzymes and transporters for the survival of the malaria parasites.

Amelia Cox

 

 


Project A3 - 2nd Cohort

TBA

EDDA KLIPP (HUB) in partnership with Alexander Maier (ANU)

Lipids – together with proteins and nucleid acids – are the major building blocks of cells. We have recently determined the lipid composition of the different life cycle stages of Plasmodium falciparum and Plasmodium berghei. Based on this data we will now determine key molecules that are important for lipid import and metabolism and explore their role and potential as drug targets. A bioinformatic overview obtained in silico will guide us to identify rate limiting steps in the lipid metabolism. These predictions will be verified using transgenic approaches using CRISPR/Cas9 and various tagging strategies. Our approaches will also determine the localization, function and importance of these enzymes and transporters for the survival of the malaria parasites.

Amelia Cox


Project A4 - 2nd Cohort

 

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Project A5 - 2nd Cohort

Metabolic Characterisation and Chemotherapeutic Targeting of Persistent T. gondii and P. falciparum Parasites

MARTIN BLUME (Robert-Koch-Institute), Kai Matuschewski (Dept. of Biology, Humboldt University Berlin), Kevin Saliba (Department Research School of Biology, ANU, Canberra)

Phenotypic variation in protozoan parasites is an important strategy to evade the immune responses and antimicrobial treatments. The apicomplexans Toxoplasma gondii and Plasmodium falciparum employ this strategy through the formation of tissue cysts and dormant blood stages, respectively [1]. These stages are marked by attenuated growth and drug resistance. The ability to persist facilitates transmission to the next host. In order to successfully target these evasive stages we need to understand how resistance to antimicrobials is achieved. To this end we aim to characterize the metabolism of dormant parasites by using untargeted metabolomics and test their susceptibility to novel inhibitors.

Thomas Andersen 


Project A6 - 2nd Cohort

Role of host lipids in the establishment of the human malaria parasite in the mosquito 

ELENA LEVASHINA (MPI) in partnership with Alexander Maier (ANU) and Martin Blume (RKI)

Establishment of Plasmodium falciparum in the mosquito is essential for malaria transmission. However, the host and mosquito factors that regulate the first steps of this critical process are not well understood. P. falciparum transmission stages represent an interesting evolutionary model of plasticity as they require a rapid parasite adaptation to fundamentally different environments (e.g. temperature, metabolites, immune system). The biological mechanisms that underlie parasite plasticity that deals with changing environment, however, remain unknown.

TBA