Our lab is interested in understanding how apicomplexan parasites scavenge nutrients from the host cells that they infect. In particular, we focus on the roles of solute transporters in nutrient scavenging. In close collaboration with the lab of Kiaran Kirk, we have identified an apicomplexan-specific family of plasma membrane-localised transporters that have key roles in the acquisition of amino acids from hosts. More recently, we have demonstrated that nutrient uptake is a highly regulated process in Toxoplasma parasites. These studies have spurred the development of in vivo approaches that examine the nutrient levels that parasites encounter in different tissues and organs across the course of an infection.
Toxoplasma parasites encounter different ionic conditions as they enter and exit host cells. Through collaborations with Adele Lehane and Kiaran Kirk, we are interested in the role of transporters in ion sensing and homeostasis in Toxoplasma parasites. These studies included understanding the mode of action of key anti-malarial compounds that target ion transporters in apicomplexans.
Our current projects examine:
- the mechanisms by which Toxoplasma parasites sense and respond to changes in amino acid levels that they encounter in different tissue and organs during infection;
- the identity and function of candidate transporters that are important for Toxoplasma proliferation;
- the role ion transporters in Toxoplasma biology and the mode of action of inhibitors that target these transporters.
Our approaches in addressing these questions include:
- identifying candidate transporter proteins;
- generating knockout or regulatable mutants in genes encoding these candidate transporters;
- examining the importance of candidate transporters for parasite proliferation and virulence;
- utilising cutting-edge physiological and biochemical assays, including protein expression in heterologous systems such as Xenopus oocytes, to characterise the roles of transporters on nutrient uptake, ion homeostasis and/or other biological processes in the parasite.
Recent papers from these project that summarise the sorts of questions we are interested in:
Rajendran E, Clark M, Goulart C, Steinhöfel B, Tjhin ET, Smith NC, Kirk K and van Dooren GG (2019) Substrate mediated regulation of the arginine transporter of Toxoplasma gondii. BioRxiv. https://doi.org/10.1101/798967
Parker KER, Fairweather SJ, Rajendran E, Blume M, McConville MJ, Bröer S, Kirk K and van Dooren GG (2019) The tyrosine transporter of Toxoplasma gondii is a member of the newly defined apicomplexan amino acid transporter (ApiAT) family. PLoS Pathogens 15(2): e1007577.
Lehane AM, Dennis ASM, Bray KO, Li D, Rajendran E, McCoy JM, McArthur HM, Winterberg M, Rahimi F, Tonkin CJ, Kirk K and van Dooren GG (2019) Characterization of the ATP4 ion pump in Toxoplasma gondii. J Biol Chem 294(14): 5720-34.
Rajendran E, Hapuarachchi SV, Miller CM, Fairweather SJ, Cai Y, Smith NC, Cockburn IA, Bröer S, Kirk K and van Dooren GG (2017) Cationic amino acid transporters play key roles in the survival and transmission of apicomplexan parasites. Nature Commun 8: 14455.