Our laboratory is interested in understanding how malaria parasites manipulate their intracellular environment in order to live within humans.
We are examining:
How the parasite enters liver cells.
How the parasite survives inside liver cells.
How the parasite is transmitted to, and develops within, mosquitoes.
Our recent research has focused on how malaria parasites commandeer red blood cells by exporting their own proteins into these cells. This has revealed potential new targets for antimalarial treatments. We are very keen to see whether these parasite targets are also active during the earliest and last phases of malaria in the human host, in order to intercept the parasite at multiple stages of its lifecycle.
We use cell biology and biochemistry to study the parasite and its interactions with the host. We also utlise the institute’s new insectary, in which Anopheles stenphensi mosquitoes are reared and can be infected with P. falciparum, P. vivax and P. berghei parasites. We use in vitro and humanised models to study malaria-host interactions across the lifecycle.
Our research also involves the development of small molecule inhibitors for use as tools to understand the role of protein export across the lifecycle, and also for potential use as antiparasitic therapies.
Australia, Griffith University, BBiomedSci (Hons), PhD
Role of plasmepsin V in gametocyte transmission to mosquitoes
Role of O-glycosylation in malaria parasite virulence
Identification of plasmepsin V as the PEXEL protease
Contribution to the discovery of PTEX (the Plasmodium translocon of exported proteins)
Development of plasmepsin V inhibitors that block protein export and kill the parasite
2014 Burnet Prize
2011 Queen Elizabeth II Fellowship, Australian Research Council
2011 Rod Rickards Fellowship, Australian Academy of Science
2011 Sir Keith Murdoch Fellowship, American Australian Association
2010 Victorian Young Tall Poppy Award for Science, Australian Institute of Policy and Science
2020 Investigator Grant, National Health and Medical Research Council
2018 Wellcome Trust Seeding Drug Discovery Grant
2017 Career Development Fellowship Level 2, National Health and Medical Research Council
2013 Young Investigator Program Grant, Human Frontier Science Program
2013, 2018 Project Grants, National Health and Medical Research Council
2017 Public Seminar, Australia & New Zealand Association for Advancement of Science
2015 Public Seminar, Hawthorn Rotary Club
2014 Public Seminar, John Macrae Centre Annual General Meeting
2014 Member of the Women in Science Parkville Precinct (WISPP)
Jennison C, Lucantoni L, O’Neill MT, McConville R, Erickson SM, Cowman AF, Sleebs BE, Avery VM, Boddey JA. Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to Mosquitoes. Cell Rep. 2019 Dec 17;29(12):3796-3806.e4. PMID: 31851913
Armistead JS, Jennison C, O’Neill MT, Lopaticki S, Liehl P, Hanson KK, Annoura T, Rajasekaran P, Erickson SM, Tonkin CJ, Khan SM, Mota MM, Boddey JA. Plasmodium falciparum subtilisin-like ookinete protein SOPT plays an important and conserved role during ookinete infection of the Anopheles stephensi midgut. Mol Microbiol. 2018 Jun 5. PMID: 29873127
Lopaticki S, Yang ASP, John A, Scott NE, Lingford JP, O’Neill MT, Erickson SM, McKenzie NC, Jennison C, Whitehead LW, Douglas DN, Kneteman NM, Goddard-Borger ED*, Boddey JA*. Protein O-fucosylation in Plasmodium falciparum ensures efficient infection of mosquito and vertebrate hosts. Nat Commun. 2017 Sep 15;8(1):561. doi: 10.1038/s41467-017-00571-y. *corresponding authors PMID: 28916755
Yang AS, O’Neill MT, Jennison C, Lopaticki S, Allison CC, Armistead JS, Erickson SM, Rogers KL, Ellisdon AM, Whisstock JC, Tweedell RE, Dinglasan RR, Douglas DN, Kneteman NM, Boddey JA. Cell Traversal Activity Is Important for Plasmodium falciparum Liver Infection in Humanized Mice. Cell Rep. 2017 Mar 28;18(13):3105-3116. doi: 10.1016/j.celrep.2017.03.017 PMID: 28355563
Boddey JA*, O’Neill MT, Lopaticki S, Carvalho TG, Hodder AN, Nebl T, Wawra S, van West P, Ebrahimzadeh Z, Richard D, Flemming S, Spielmann T, Przyborski J, Babon JJ, Cowman AF*. Export of malaria proteins requires co-translational processing of the PEXEL motif independent of phosphatidylinositol-3-phosphate binding. Nat Commun. 2016 1;7:10470. doi: 10.1038/ncomms10470. *corresponding authors PMID: 26832821
Coffey MJ, Sleebs BE, Uboldi AD, Garnham AL, Franco M, Marino ND, Panas MW, Ferguson DJ, Enciso M, O’Neill MT, Lopaticki S, Stewart RJ, Dewson G, Smyth GK, Smith BJ, Masters SL, Boothroyd JC, Boddey JA*, Tonkin CJ*. An aspartyl protease defines a novel pathway for export of Toxoplasma proteins into the host cell. Elife. 2015 4:e10809. doi: 10.7554/eLife.10809. *corresponding authors PMID: 26576949
Hodder AN, Sleebs BE, Czabotar PE, Gazdik M, Xu Y, O’Neill MT, Lopaticki S, Nebl T, Triglia T, Smith BJ, Lowes K, Boddey JA*, Cowman AF*. Structural basis for plasmepsin V inhibition that blocks export of malaria proteins to human erythrocytes. Nat Struct Mol Biol. 2015 Aug;22(8):590-6. doi: 10.1038/nsmb.3061. Epub 2015 Jul 27. *corresponding authors. PMID: 26214367
Sleebs BE, Lopaticki S, Marapana DS, O’Neill MT, Rajasekaran P, Gazdik M, Gunther S, Whitehead LW, Lowes KN, Barfod L, Hviid L, Shaw PJ, Hodder AN, Smith BJ, Cowman AF, Boddey JA. Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites. PLoS Biol. 2014 Jul;12(7):e1001897. PMID: 24983235.
Boddey JA, Hodder AN, Gunther S, Gilson PR, Patsiouras H, Kapp EA, Pearce JA, de Koning-Ward TF, Simpson RJ, Crabb BS, Cowman AF. An aspartyl protease directs malaria effector proteins to the host cell. Nature. 2010 Feb 4;463(7281):627-31. PMID: 20130643.
de Koning-Ward TF, Gilson PR, Boddey JA, Rug M, Smith BJ, Papenfuss AT, Sanders PR, Lundie RJ, Maier AG, Cowman AF, Crabb BS. A newly discovered protein export machine in malaria parasites. Nature. 2009 Jun 18;459(7249):945-9. PMID: 19536257.
A fundamental step in human infection by P. falciparum is the traversal and invasion of human hepatocytes. The molecular basis for these interactions is almost completely unknown.
This project uses genetic techniques to tag or disrupt proteins that may be involved in these processes and to examine the consequences on the parasite and host at the subcellular and cellular level. A clearer understanding of how parasites interact with human hepatocytes will allow us to augment it for downstream applications as well as to potentially block it for therapeutic purposes.
Team members: Annie Yang, Matthew O’Neill, Sash Lopaticki
The protein export pathway has been studied most in the blood stage of malaria. This project investigates whether the export pathway used to remodel erythrocytes is employed during liver infection by P. falciparum and P. berghei parasites. The project involves molecular parasitology and cell biology using in vitro and humanised models.
The second component of this project investigates whether the export pathway in malaria parasites is also employed by the closely related Apicomplexan parasite, Toxoplasma gondii, which is a parasite of cats and humans and causes mental ilnesses.
Team members: Pravin Rajasekaran, Matthew O’Neill, Michael Coffey
Exported proteins play a variety of roles in the infected erythrocyte; do exported proteins also play key roles at other stages of the lifecycle?
This project involves the development of transgenic P. falciparum and P. berghei parasites with proteins tagged or deleted and examining the functional consequences of the deletion on parasite transmission and development, from gametocytes through to liver stage forms. It also involves defining the subcellular localization of the proteins across the lifecycle.
Team members: Jennifer Armistead, Pravin Rajasekaran, Charlie Jennison, Matthew O’Neill, Sash Lopaticki
Plasmepsin V processing of the PEXEL can be blocked with inhibitors.
This project is to develop a second-generation small molecule inhibitor with the hope that it is effective in vivo and in humans. The project uses structure-guided medicinal chemistry to develop small molecule leads into plasmepsin V inhibitors for use in cell biological studies across the lifecycle as well as in humans. The project involves medicinal chemistry and chemical biology as well as structural biology, cell biology and molecular parasitology.
Team members: Brad Sleebs, Michelle Gazdik, Matthew O’Neill, Sash Lopaticki