Apicomplexa are intracellular parasites that severely impact human health and economic prosperity in Australia and around the world. They include the malaria-causing parasite Plasmodium and the opportunistic pathogen Toxoplasma gondii. Our focus is predominantly on Toxoplasma, since the types of questions we are addressing are usually easiest to answer in this organism, although we collaborate extensively with the highly integrated malaria research community at ANU to translate our studies into Plasmodium parasites.
The objective of the ANU Toxo lab is to gain a better understanding of how apicomplexans acquire nutrients from the host cells in which they reside, and how they then convert these nutrients into the molecular building blocks the parasites need to proliferate. We are interested in identifying and characterising compounds that inhibit these processes, with a view to developing new treatment options against these formidable foes. Independently-minded, hard-working students interested in joining our group should contact Giel van Dooren. Students will gain experience in diverse and cutting-edge molecular, physiological and cell biological approaches for studying parasite biology, as well as receiving training in data analysis and scientific writing. We will be recruiting two research officers/assistants to our group as part of NHMRC- and ARC-funded research projects in early 2020. Contact Giel van Dooren for more details.
The lab currently studies three major areas of apicomplexan biology:
- Nutrient acquisition: How do apicomplexan parasites steal nutrients from the host cells in which they reside? We focus on the role that plasma membrane-localised solute transporters play in these processes. We utilise the facile genetics of Toxoplasma to uncover essential transporters, and then use a broad range of physiological, biochemical, metabolomic, imaging, and heterologous expression approaches to elucidate the function(s) of these transporters. Increasingly, we are becoming interested in how nutrient acquisition changes in the different tissues and organs that parasites inhabit across the course of an infection. To examine these processes we use in vivo mouse infection models. We are in a terrific research environment to characterise the functions of novel transporters, and collaborate extensively with the groups of Kiaran Kirk and Adele Lehane on these projects.
- Mitochondrial biology: What roles do parasite mitochondria play in proliferation and virulence of these pathogens? We are interested in novel features of the mitochondrial electron transport chain, which is a major drug target in apicomplexans, including in identifying and characterising novel inhibitors of this pathway. We are also interested in how mitochondrial metabolism is integrated into the broader metabolism of these parasites, including in the metabolic relationships between the mitochondrion and apicoplast (a reduced, chloroplast-derived organelle) of these parasites. Our studies in this area use a broad range of physiological, biochemical and cell biological approaches to study mitochondrial biology in both Toxoplasma and Plasmodium, the latter studies conducted in collaborations with Alex Maier and Kevin Saliba.
- The life cycle of Toxoplasma parasites: The sexual stages of the Toxoplasma life cycle occur exclusively in felids. In close collaboration with visiting professor Nick Smith from the University Technology Sydney, we are interested in understanding the genes and processes that are required for parasites to complete their life cycles in their felid hosts. We use modern genetic, in vitro and in vivo infection approaches to study sexual stage biology of Toxoplasma.
Tjhin ET, Hayward JA, McFadden GI and van Dooren GG (2020) Characterization of the apicoplast-localized enzyme TgUroD in Toxoplasma gondii reveals a key role of the apicoplast in heme biosynthesis. J Biol Chem: in press.
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
Hayward JA and van Dooren GG (2019) Same same, but different: uncovering unique features of the mitochondrial respiratory chain of apicomplexans. Mol Biochem Parasitol 232: 111204.
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.
Seidi A, Muellner-Wong LS, Rajendran E, Tjhin ET, Dagley LF, Aw VY, Faou P, Well AI, Tonkin CJ and van Dooren GG (2018) Elucidating the mitochondrial proteome of Toxoplasma gondii reveals the presence of a divergent cytochrome c oxidase. eLife e38131.
Huet D, Rajendran E, van Dooren GG and Lourido S (2018) Identification of cryptic subunits from an apicomplexan ATP synthase. eLife e38097.
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.
van Dooren GG, Yeoh LM, Striepen B and McFadden GI (2016) The import of proteins into the mitochondrion of Toxoplasma gondii. J Biol Chem 291(37): 19335-50.
Warring SD, Dou Z, Carruthers VB, McFadden GI and van Dooren GG (2014) Characterization of the chloroquine resistance transporter homologue in Toxoplasma gondii. Eukaryot Cell 13(11): 1360-70.
Katris, NJ, van Dooren GG, McMillan PJ, Hanssen E, Tilley L and Waller RF (2014) The apical complex provides a regulated gateway for secretion of invasion factors in Toxoplasma. PLoS Pathogens 10(4): e1004074.
van Dooren GG and Striepen B (2013) The algal past and parasite present of the apicoplast. Annu Rev Microbiol 67: 271-89-12.
Glaser S§, van Dooren GG§, Agrawal S, Brooks CF, McFadden GI, Striepen B and Higgins MK (2012) Tic22 is an essential chaperone required for protein import into the apicoplast. J Biol Chem 287(47): 39505-12 §contributed equally
Brooks CF§, Johnsen H§, van Dooren GG§, Muthalagi M, Lin SS, Bohne W, Fischer K and Striepen B (2010) The Toxoplasma apicoplast phosphate translocator links cytosolic and apicoplast metabolism and is essential for parasite survival. Cell Host Microbe 7(1): 62-73. §contributed equally
van Dooren GG, Reiff SB, Tomova C, Meissner M, Humbel BM, Striepen B (2009) A novel dynamin-related protein has been recruited for apicoplast fission in Toxoplasma gondii. Curr Biol 19(4): 267-276.
van Dooren GG, Tomova C, Agrawal S, Humbel BM, Striepen B (2008) Toxoplasma gondii Tic20 is essential for apicoplast protein import. Proc Natl Acad Sci USA, 105(36): 13574-13579.
Chtanova T, Schaeffer M, Han SJ, van Dooren GG, Nollmann M, Herzmark P, Chan SW, Satija H, Camfield K, Aaron H, Striepen B, Robey EA (2008) Dynamics of neutrophil migration in lymph nodes during infection. Immunity 29(3): 487-496.
van Dooren GG, Marti M, Tonkin CJ, Stimmler LM, Cowman AF, McFadden GI (2005) Development of the endoplasmic reticulum, mitochondrion and apicoplast during the asexual life cycle of Plasmodium falciparum. Mol Microbiol 57(2): 405-419.
Ralph SA, van Dooren GG, Waller RF, Crawford MJ, Fraunholz MJ, Foth BJ, Tonkin CJ, Roos DS, McFadden GI. (2004) Metabolic maps and functions of the Plasmodium falciparum apicoplast. Nat Rev Microbiol 2(3): 203-16.
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