Mission
The mission of the Department of Drug Resistance Diagnostics is:
- to improve knowledge in the development, survival and spread of drug resistance in malaria parasites
- to monitor the extent of drug resistance and efficacy of standard and new anti-malarial drugs in areas of interest to the Australian Defence Force (ADF).
The department explores and evaluates novel malaria detection/diagnosis methods including molecular and various rapid diagnostic kits. The department is engaged in studies investigating P. vivax genetics that determine or correlate with relapses of infections.
Current research projects
Mechanisms of resistance to standard and newly developed antimalarial drugs
- Chloroquine resistance in P. falciparum: mutations in P. falciparum chloroquine resistant transporter (Pfcrt) and their roles in conferring chloroquine resistance
- Chloroquine resistance in P. vivax: searching for molecular correlates for chloroquine resistance in P. vivax and its correlation with in vivo and in vitro susceptibility to chloroquine (in collaboration with Menzies School of Health Research)
- Atovaquone resistance in P. falciparum: established that genetic mutations resulted from atovaquone selection are located in the drug binding site in cytochrome b and correlate with resistance to atovaquone. The implications of these mutations in resistance to Malarone are under investigation.
- Sulfa resistance in P. vivax: Using molecular biology methods and molecular modelling, we established that mechanism of innate resistance to sulfa drugs in P. vivax is determined by a single amino acid in the drug binding site in pvDHPS. P. vivax can also acquire resistance to sulfa drugs by changing several other amino acids at the drug binding site. Further investigations are under way to examine the effect of these mutations in P. falciparum systems and to test a variety of sulfa drugs on PvDHPS in this system.
- Antifolate resistance in P. vivax. Investigations of genetic mutations in P.vivax DHFR and DHPS and their impact on the susceptibilities to conventional and new antimalarial antifolate drugs are underway using the state of art transfection technology.
- Artemisinin resistance: Investigating the development of parasites following exposures to artemisinin derivatives and possible linkage with treatment failures (in collaboration with University of South Florida, USA).
- Primaquine tolerance in P. vivax: genetic analysis on parasites breaking through primaquine radical cure.
Molecular evaluation of antimalarial drugs and drug combinations trailing in various settings
In collaboration with MERLIN, the department has performed molecular analysis on parasite diversity and allelic types for a chloroquine and Fansidar trial in East Timor, providing information on malaria transmission in the area and more accurate efficacy data by distinguishing new infections from recrudescences.
Evolution of drug resistance
- Monitor chloroquine resistance and investigate the evolution of chloroquine resistance in Asia-Pacific Region and other regions of interest (in collaboration with WRAIR, JIPD and HPITD China).
- Monitor the extent of sulfadoxine and pyrimethamine (SP) resistance in P. vivax: investigate mutations in P. vivax DHFR and DHPS in parasites collected from Asia, South-East Asia and Pacific regions and their association with in vitro susceptibility to SP.
- Role of antigenic variation in the development, survival and spread of drug resistance (NIH funded project): Investigating antigenic switch rates and switch processes in P. falciparum, and the influence of antigenic variation on the development, survival and spread of drug resistance by using molecular biology methods and mathematical modelling.
P. vivax genetics and relapses
Despite the use of radical cure regimens, post operational relapses of P. vivax infections in ADF personnel have become a major health problem. Studies in parasite genetics are under way to investigate factors that associated with increased risk of relapses.
Improve rapid malaria diagnostic tests
Many rapid diagnostic tests (RDTs) for P. falciparum have been developed and are commercially available. Most of these RDTs are based on detecting parasite antigens in patient's blood. The detection sensitivity of these kits is highly variable. In collaboration with WPRO/WHO and FIND we are investigating the possible causes of the sensitivity variation. Our research focus on defining genetic diversity in parasite antigens, difference in the level of antigens produced by parasites and the variation in epitopes recognised by monoclonal antibodies. The study outcome will help the selection and quality control of RDTs, as well as help to improve the detection sensitivity of malaria RDTs .
Molecular Diagnosis
For assisting microscopic confirmation of malaria infections, we have established PCR-based detection for 4 human malaria species. We will continue to improve out capacity to perform multiplex PCR and develop field adaptable PCR methods. Currently, the department is actively involved in the AusAID Pacific Malaria Initiatives. We are investigating the prevalence of the malaria infections and the transmission parameters in Vanuatu and Solomon Islands using molecular tools.
Training
- Postgraduates: Hons, Masters and PhD;
- Short term training for scientists from developing countries: Molecular- based techniques: PCR, genotyping, and resistance mutation detections;
- Microscopic confirmation of malaria infections for ADF
Collaborators
Australian
- Malaria Drug Resistance and Chemotherapy, Clinical Tropical Medicine, and Malaria Biology, Queensland Institute of Medical Research
- School of Population Health, the University of Queensland.
- Tropical Medicine and International Health Unit, Menzies School of Health Research, Darwin.
International
- WPRO/WHO/FIND
- National Institutes of Health
- Department of Global Health, University of South Florida, Tampa, USA
- Division of Experimental Therapeutics, Walter Reed Army Institute of Research, USA.
- Research Institute for Tropical Medicine, Manila, Philippines
- Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
- Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
- Genome Sciences, University of Washington, Seattle, WA, USA.
- Malaria Department, Jiangsu Institute for Parasitic Diseases, China
- Hainan Provincial Institute for Tropical Diseases, Hainan CDC, China
- Malaria Department, Henan CDC, Zhengzhou, China
- National Institute of Health Research and Development, Ministry of Health, Jakarta, Indonesia
External Grants
- NIH, RO1, 2000-2003; 2004-2007; 2005-2009
- WPRO/WHO, 2004-2005, 2005 - 2007
- WHO/ FIND, 2007- 2008
- TDR/WHO, 2002-2004