Malaria Biology
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Collaborators
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Key Publications
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Lab Head: Dr Donald Gardiner
donG@qimr.edu.au
There are an estimated 300-500 million malaria infections each year, resulting in over 1 million deaths, predominantly in children under 5 years of age and mainly in Africa. Malaria parasites have developed resistance to all classes of antimalarial drugs. Mosquito vectorsresistant to insecticides,have also arisen. As current control measures are becoming less effective, new approaches to improve the control and treatment of malaria are needed. New antimalarials that act against novel parasite targets are required to combat multi-drug resistant parasites. The focus of the Malaria Biology Laboratory is to understand the molecular and cellular processes involved in critical phases of the parasite life cycle. Armed with this knowledge we aim to identify novel drug targets that can be rationally exploited to improve the control and treatment of malaria.
Antiretroviral Protease Inhibitors
The global epidemiology of HIV and malaria significantly overlap, with the majority of HIV-infected individuals living in regions of the
world susceptible to malaria (~25.4 million HIV-infected individuals live in sub-Saharan Africa). Recent studies have indicated that the
interaction between HIV and malaria infection is bi-directional and synergistic. Pregnant women are particularly vulnerable to the adverse
effects of co-infection.
Given this overlapping epidemiology and the rollout of highly active antiretroviral therapy (HAART), it is likely that many patients with
HIV on HAART will inevitably be exposed to malaria. While the effects of antiretroviral therapy on the outcome of malaria infection have
yet to be defined, recent studies have highlighted the importance of understanding these interactions. We have recently shown that a
number of antiretroviral drugs of the protease inhibitor class (APIs) can kill malaria parasites at clinically relevant concentrations (see table).
The significance of this observation is two fold: it represents the identification of a novel group of antimalarial agents, and it likely
has important implications for the treatment of people who are co-infected with malaria and HIV.
The mechanism responsible for the antimalarial activity of the APIs is not known. We hypothesize that similar to their action against HIV that the APIs act on an aspartyl protease in malaria. Our current data suggest that one or more of a group of aspartyl proteases (plasmepsins, PMs) not present in the parasite food vacuole (the site of haemoglobin digestion) is the target of these drugs in the malaria parasite. We know very little about these enzymes and in addition to better defining the in vivo antimalarial activity of APIs in co-infected individuals, we are currently exploring the biology of these enzymes in an effort to define the mechanism of API antimalarial activity.
Amino peptidases and malaria
Now that the human and malaria genome sequences have been completed and published we are presented have the necessary information
to explore and improve our understanding of malaria and as a result to rationally design drugs to specific parasite targets.
In conjunction with our collaborator Prof. John Dalton we are investigating the malarial amino-peptidases as potential antimalarial drug targets. We are specifically interested in four of these enzymes, the leucine aminopeptidase, the membrane alanyl aminopeptidase, the aspartyl aminopeptidase and the prolyl aminopeptidase. These enzymes are believed torelease amino acids from protein substrates in malaria cells. Because of their central role in parasite protein turnover they are targets at which novel anti-malaria drugs can be directed. In conjunction with the National Institutes of Health in America we will be performing high throughput screening of small chemical libraries to identify novel inhibitors of these enzymes.
GATEWAY Vectors and P. falciparum Transfection
Our research group has been involved in improving both malaria transfection vectors and the transfection
technique itself. In 2003 we published the first group of Gateway™ compatible P. falciparum vectors (link to
gateway page). Although our vectors have changed since this original publication, today we routinely use
Gateway™ compatible vectors to build all of our transfection constructs.
Commitment and sex inPlasmodium falciparum
Gametocytogenesis is a poorly understood stage of the malaria parasite life cycle. It is essential for transmission of the parasite
from the human to the mosquito host and represents a potential focus for strategies to reduce the burden of malaria infection.
In collaboration with Dr Katharine Trenholme, the Malaria Biology Laboratory is studying various aspects of this important life
cycle stage including transcription factors necessary for gametocyte gene expression and the switch from asexual replication to
the production of gametocytes. The basis of this switch is unknown but this has been shown to be sensitive to environmental stimuli,
and thus a cell signalling pathway between the environment and the parasite, leading to transcriptional control, must be involved.
We are looking at the signalling mechanisms leading to commitment to gametocytogenesis which in addition to providing important
information about the basic biology of the parasite also has the potential to identify compounds for the treatment of malaria or
for reduction of transmission. We are also examining the effects of antimalarial drugs on gametocyte production, as number of
currently used antimalarial drugs have been shown to increase gametocyte production and this may have important implications
for the transmission and spread of drug resistant malaria parasites.
Staff
| Laboratory Head: | Dr Don Gardiner |
| University of Queensland Post-doctoral Fellow: |
Dr Tina Skinner-Adams |
| PhD student: | Chris Peatey |
| Undergraduate Student: | Joanne Lim |
To see staff contact details, please type name below and hit Enter
Funding
Research in this laboratory is currently funded by The National Health and Medical Research Council of Australia, The Australian Research Council, The ANZ Trust and The National Institutes of Health (USA). We also acknowledge the generosity of Mark Nicholson, Alice Hill and the Tudor Foundation.
Collaborators
NATIONAL- Assoc/Prof. James McCarthy. Clinical Tropical Medicine Laboratory, Queensland Institute of Medical Research. Brisbane, Queensland.
- Dr Katharine Trenholme. Malaria and Scabies Laboratory, Queensland Institute of Medical Research. Brisbane, Queensland.
- Dr Kathy Andrews. Clinical Tropical Medicine Laboratory, Queensland Institute of Medical Research. Brisbane, Queensland.
- Prof John Dalton. Institute for the Biotechnology of Infectious Diseases University of Technology Sydney (UTS).
- Mr John Ray. St Vincents Hospital, Sydney.
- Dr Kabada Sriprakash. Menzies School of Health Research, Darwin and The Queensland Institute of Medical Research, Brisbane, Queensland.
- Dr Nick Anstey. Menzies School of Health, Darwin. Northern Territory.
- Dr Catherine Hyland. Australian Red Cross Blood Transfusion Service, Brisbane.
- Professor Leann Tilley. Department of Biochemistry, La Trobe University, Melbourne.
- Dr Rowena Martin. Australian National University, Canberra
- Prof. J de Jerdey, Dr. L Guddat & D Keogh. School of Molecular and Microbial Sciences, the University of Queensland, Brisbane.
- Dr C Brown. School of Bio-molecular and Physical Sciences, Nathan Campus, Griffith University, Brisbane.
- Dr R Price. Menzies School of Health Research, Darwin.
INTERNATIONAL
- Dr Colin Sutherland. London School of Tropical Health and Hygiene. London UK.
- Dr Lisa Ranford-Cartwright. Glasgow University. Glasgow. UK.
- Dr Colin Berry. Cardiff University, Wales, UK.
- Dr Joanne Thompson. Edinburgh University, Scotland.
- Dr Angus Bell. Trinity College Dublin, Ireland.
- Dr Tobias Spielman. Tropical Institute, Hamberg Germany.
Student Projects
Research projects are available within the Malaria Biology Laboratory
for both B.Sc. Honours and Ph.D. students working in the malaria. Please
contact a staff member for additional information.
Key Publications
Andrews KT, Fairlie DP, Madala PK, Ray J, Wyatt DM, Hilton PM, Melville LA, Beattie L, Gardiner DL, Reid RC, Stoermer MJ, Skinner-Adams T, Berry C, McCarthy JS. Potencies of human immunodeficiency virus protease inhibitors in vitro against Plasmodium falciparum and in vivo against murine malaria. Antimicrob. Agents Chemother. 2006 Feb;50(2):639-48.Spielmann, T, Gardiner, DL, Beck, HP, Trenholme, KR, Kemp DJ. Organisation of ETRAMPs and EXP-1 at the parasite-host cell interface of malaria parasites. Mol. Micro. 2006 Feb;59(3):779-94.
Gardiner DL, Trenholme KR, Skinner-Adams TS, Stack CM and Dalton JP.. Over-expression of Leucyl Aminopeptidase in Plasmodium falciparum Parasites: Target for the Anti-Malaria Activity of Bestatin. J. Biol. Chem. 2006 Jan 20;281(3):1741-5.
Spielmann T, Hawthorne PL, Dixon MWA, Hannemann M, Klotz K, Kemp DJ, Klonis N, Tilley L, Trenholme KR, and Gardiner DL. A cluster of ring stage-specific genes linked to a locus implicated in cytoadherence in Plasmodium falciparum codes for PEXEL negative and PEXEL positive proteins exported into the host cell. Mol Biol Cell. 2006;17(8):3613-24.
Spielmann T, Dixon MWA, Hernandez-Valladares M, Hannemann M, Trenholme KR, and Gardiner DL. Reliable transfection of Plasmodium falciparum using non-commercial plasmid mini preparations. Int. J. Parasitol. 2006 Oct;36(12):1245-8.
Skinner-Adams T.S., Andrews K. T., Melville L ,McCarthy J. & Gardiner D.L. Synergistic interactions of antiretroviral protease inhibitors saquinavir and ritonavir with chloroquine and mefloquine against Plasmodium falciparum in vitro. Antimicrob. Agents Chemother. 2007 51(2):759-62.
Redmond, AM.; Skinner-Adams, TS.; Andrews, KT; Gardiner, DL.; Ray, J.; Kelly, M; McCarthy, JS Antimalarial activity of sera from subjects taking HIV protease inhibitors. AIDS 2007;21:763-765.
Stack CM , Lowther J, Cunningham E, Donnelly S, Gardiner DL, Trenholme KR, Skinner-Adams TS, Teuscher F, Grembecka J, Mucha A, Kafarski P, Lua L, Bell A, and Dalton JP. Characterisation of the Plasmodium falciparum M17 leucyl aminopeptidase: a protease involved in amino acid regulation with potential for antimalarial drug development. J Biol Chem. 2007 19;282(3):2069-80
Teuscher F Lowther J, Skinner-Adams TS, Spielmann T, Dixon M, Stack CM, Donnelly S, Mucha A, Kafarski K, Vassiliou K, Gardiner DL. Dalton JP, TrenholmeKR. The M18 Aspartyl Aminopeptidase Of The Human Malaria Parasite Plasmodium falciparum. J. Biol. Chem. 2007 Oct 19;282(42):30817-26.
Skinner-Adams TS, Lowther J, Teuscher F, Stack CM, Grembecka J Mucha A, Kafarski P, Trenholme KR, Dalton JP, Gardiner DL. Identification of phosphinate inhibitors directed against the Plasmodium falciparum M17 leucine aminopeptidase. J. Med. Chem. 2007. Nov 29;50(24):6024-31.
Andrews KT, Gatton ML Skinner-Adams TS, McCarthy, JS, Gardiner, DL. HIV-malaria interactions: don't forget the drugs." Science. 2007 315: 1791.
Dixon M, Thompson J, Gardiner DL, & Trenholme KR. Sex In Plasmodium - A sign of Commitment. Trends Parasitol. 2008 Mar 12; [Epub ahead of print]
Skinner-Adams TS, McCarthy JS , Gardiner DL & Andrews KT. HIV and malaria co-infection: Interactions and consequences of chemotherapy. Trends Parasitol. 2008