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 aim of this project is to develop an integrated mathematical model for ion and cell volume homeostasis in the malaria parasite-infected human erythrocyte. This model will be an invaluable tool in understanding the mechanism of action of the growing number of ‘ion-disrupting’ antimalarials that are emerging from high throughput phenotypic screens.

Edda Klipp and colleagues (HUB) have recently developed a generalized thermodynamic description of the complex interplay of the plasma membrane ion transporters, membrane potential and the consumption of energy for maintaining specific intracellular ion concentrations [1]. The model has been applied to ion homeostasis in the cells of the yeast Saccharomyces cerevisiae, and includes passive ion fluxes driven by electrochemical potential differences, as well as secondary active transport processes involving the complex interplay of different ions (symport, antiport) and primary active transporters, energized by the hydrolysis of ATP (ATPases).

Kiaran Kirk, Adele Lehane and colleagues (ANU) have developed a range of physiological and biochemical techniques to characterize the mechanisms (channels, transporters, pumps) involved in ion regulation in the malaria parasite and its host cell [2].  Using these methods they have:  (i) measured the concentrations of a range of ions in the parasite cytosol (Na+, K+, Cl-, Ca2+, H+) and host erythrocyte (Na+, K+);  (ii) measured and characterized the transport of these ions across the parasite plasma membrane and parasitized erythrocyte membrane;  (iii) measured the membrane potential, volume and ‘buffering power’ of the intraerythrocytic parasite. Their work has led to the identification of a Na+ pump on the parasite plasma membrane, postulated to be the primary target of the new spiroindolone antimalarial KAE609 (now in Phase II clinical trials) [3].

In this project the framework used by Klipp’s group in developing the yeast cell model will be adapted to the parasitized erythrocyte, taking into account its ‘two compartment’ nature and incorporating the quantitative physiological data from the Kirk/Lehane lab. The model will incorporate the flux of ions across both the erythrocyte and parasite plasma membranes.

There will be up to two students working on this project simultaneously. The modelling will guide the experimental strategy, and the experimental data generated will be incorporated into the model, in an iterative process. The initial phase of formulating the model (done under the supervision of Prof Klipp) will reveal what additional data might be needed in order to constrain the model and this will determine the initial physiological measurements to be undertaken in the Kirk/Lehane lab at the ANU. The model will be developed and refined by assessing its ability to predict the changes in a range of physiological parameters seen in response both to perturbations of the extracellular ionic environment (imposed by changing the ionic composition of the extracellular solution) and to the addition of chemical agents that perturb ion homeostasis (ion transport inhibitors and activators).

The project will yield the first integrated model of ion homeostasis in the malaria parasite infected erythrocyte. Malaria parasite ion transport pathways have recently emerged as high-potential antimalarial drug targets and the model will provide a wealth of new insights into the mechanism of action of ion transport inhibitors in the parasite.

Interlinkages: Giel van Dooren (ANU), Alexander Maier (ANU), Christina Spry (ANU), Kevin Saliba (ANU), Kai Matuschewski (HUB)

References:

(1) Gerber, S. et al. (2016). PLoS Comput. Biol. 12: e1004703

(2) Kirk, K. (2015). Ann. Rev. Microbiol. 69: 341–359

(3) Spillman, N.J. et al. (2013). Cell Host Microbe 13: 227–237