Malaria Drug Resistance and Chemotherapy Laboratory
Staff
Funding
Collaborators
Student Projects
Key Recent Publications
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Lab Head: Dr Qin Cheng
The research conducted within the Malaria Drug Resistance and Chemotherapy Laboratory focuses on improving our knowledge of the development, survival and spread of drug resistance in parasites causing human malaria. Plasmodium falciparum and Plasmodium vivax are responsible for millions of deaths annually in tropical regions of the world. Although our understanding of the biology of the parasite has increased in recent years, the number of malaria- associated deaths continues to rise. This is largely due to the development of parasite resistance to most of the commonly used anti-malarial drugs. Effective treatment of malaria remains one of the largest global health challenges, especially since the cost of newer anti-malarial drugs far exceeds what many malaria affected countries can afford.
CURRENT PROJECTS
1. Antigenic variation and drug resistance
P. falciparum parasites undergo antigenic variation by which they continually change the phenotype of proteins
expressed on the surface of infected red blood cells; proteins to which the host immune system is exposed.
This project investigates 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 biological
methods and mathematical modelling.
2. Parasite resistance to artemisinin drugs
The artemisinin derivatives are currently the most promising therapy to treat multi-drug resistant malaria. Although
resistance to artemisinin drugs has not yet been observed in the field, experiences with all other anti-malarial
drugs indicate that there is a real risk of parasites developing resistance to these. The potential mechanisms of
artemisinin resistance in laboratory selected parasites are currently the focus of this project.
3. Accuracy of rapid malaria diagnostic tests
Many rapid diagnostic tests (RDTs) for P. falciparum have been developed and most of these RDTs are based on
detecting parasite HRPII antigen in patient's blood. Detection sensitivity of these kits is highly variable.
We are investigating the genetic diversity of parasite HRPII in various countries and its effect on detection
sensitivity of RDTs. The study outcome will improve detection sensitivity for HRPII-based RDTs for P. falciparum
thereby assisting with the timely and correct diagnosis of malaria.
4. Mechanisms of resistance to standard and newly developed antimalarial drugs
We are investigating the genetic changes causing chloroquine, Fansidar, mefloquine and atovaquone resistance in P. falciparum,
and the evolution of the resistant parasites in the Asia-Pacific region. The outcome provides better understanding on how
malaria parasites develop resistance to drugs and how resistance spread, as well as guiding treatment policy.
5. Assesing the impact of malaria interventions
Using theoretical mathematical models, we are simulating the impact of various malaria interventions on the long-term clinical and
parasitological profile of falciparum malaria endemic regions. This work provides a theoretical basis for comparing intervention
strategies and assessing ways of providing cost-effective control strategies.
6. Plasmodium vivax genetics that determine relapses and drug resistance
Despite the use of radical cure regimens, relapses of P. vivax infections have become a major health problem. P. vivax has also developed
significant resistance to chloroquine and pyrimethamine. Studies in parasite genetics are under way to investigate factors that are
associated with increased risk of relapses and correlate with chloroquine, pyrimethamine resistance.
Staff
| Labhead: | Dr Qin Cheng | |
| Deputy Head: | Dr Michelle Gatton | |
| Research Officer: | Dr Franka Teuscher Dr Andrea Codd |
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| Research Assistants: | Ms Karryn Gresty Ms Anita Pelecanos |
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| Visiting Scientists: | Dr Marina Chavchich Dr Norm Waters Professor Dennis Shanks | marina.chavchich@defence.gov.au Norm.Waters@defence.gov.au dennis.shanks@defence.gov.au |
| PhD Students: | Alyson Auliff, BSc (Hons) Joanne Baker, BSc | alyson.auliff@defence.gov.au joanne.baker1@defence.gov.au |
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Funding
National Institutes of Health (USA)AusAid through WHO/WPRO
Collaborators
National- Drs James McCarthy, Don Gardiner, Katharine Trenholme, Kathy Andrews, Peter Ryan and Prof Brian Kay at QIMR.
- Drs Ric Price and Nick Anstey, Tropical Medicine and International Health Unit, Menzies School of Health Research, Darwin
- Dr Mike O'Neil, Bob Cooper and Prof Dennis Shanks, Australian Army Malaria Institute,
- Dr Damon Eisen, Melbourne Hospital, Melbourne
International
- Prof Dennis Kyle, Department of Global Health, University of South Florida, Tampa, FL, USA.
- Drs Mike O'Neil, Chris Ockenhouse, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, USA.
- Prof John Adams, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.
- WHO/WPRO and TDR: The Malaria Rapid Diagnostic Tests Quality Assurance program and network.
- Prof Carol Sibley, Genome Sciences, University of Washington, Seattle, WA USA.
- Prof Nicholas J White, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Student Projects
A number of research projects are available for B.Sc. Honours and PhD students who are interested in the mechanism and evolution of drug resistance in malaria parasites. Please contact Dr Qin Cheng.
Key Publications
(since 2000)Korsinczky M., Chen N., Kotecka B., Saul A., Rieckmann K. and Cheng Q. (2000) Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located in a putative drug-binding site. Antimicrob. Agent Chemocher. 44(8):2100-2108.
Chen, N., Russel, B., Staley, J., Kotecka, B., Nasveld, P. and Cheng, Q. (2001) Sequence polymorphisms in pfcrt are strongly associated with chloroquine resistance in Plasmodium falciparum. J. Infect. Dis. 183(10):1543-1545.
Fowler, E., Peters, J., Gatton, M., Chen, N. and Cheng, Q. (2002) Genetic diversity of the DBL? region in Plasmodium falciparum var genes among Asia-Pacific isolates. Mol Biochem Parasitol 120(1):117-126.
Chen, N., Russel, B., Fowler, E., Peters, J. and Cheng, Q. (2002) Levels of chloroquine resistance in Plasmodium falciparum are determined by loci apart from Pfcrt and Pfmdr1. J. Infect. Dis. 185 (3):405-406.
Gatton, M.L.and Cheng, Q. (2002) Evaluation of the pyrogenic threshold for P. falciparum malaria in naïve individuals. Am. J. Trop. Med. Hyg. 66(5):467-473.
Peters, J., Chen, N., Gatton, M., Korsinczky, M., Fowler, E., Manzetti, S., Saul, A. and Cheng. Q. (2002) Mutations in cytochrome b resulting atovaquone resistance are associated with a loss of fitness in Plasmodium falciparum. Antimicrobial Agents and Chemotherapy 46(8):2435-2441.
Peters, J., Fowler, E., Gatton, M., Chen, N., Saul, A. and Cheng, Q. (2002) High diversity and rapid changeover of expressed var genes during acute phase of Plasmodium falciparum infections in human volunteers. Proc. Nat. Acad. Sci. USA. 99(16):10689-10694.
Chen, N., Baker, J., Ezard, N., Burns, M., Edstein, M. and Cheng, Q. (2002) Molecular evaluation of the efficacy of chloroquine treatment of uncomplicated Plasmodium falciparum in East Timor. Am. J. Trop. Med. Hyg. 67(1):64-66.
Tjitra, E., Baker, J., Cheng, Q and Anstey, N. (2002) The therapeutic efficacy of artesunate plus sulfadoxine- pyrimethamine and chloroquine plus sulfadoxine-pyrimethamine for vivax malaria: relationship with Plasmodium vivax dhfr mutations. Antimicrobial Agents and Chemotherapy 46(12):3947-3953.
Gatton, M.L., Peters, J., Fowler, E. and Cheng, Q. (2003) The switching rates of Plasmodium falciparum var genes: faster than we thought? Trends in Parasitology 19(5):202-208.
Chen, N., Kyle, D.E., Pasay, C.M. Fowler, E.V., Peters, J. M. and Cheng, Q. (2003) Pfcrt allelic types with novel amino acid mutations in chloroquine resistant Plasmodium falciparum from the Philippines. Antimicrobial Agents and Chemotherapy 47(11):3500-3505.
Gatton, M. L. and Cheng. Q. (2004) Investigating antigenic variation and other parasite-host interactions in Plasmodium falciparum infections in naïve hosts. Parasitololgy 128:367-376.
Korsinczky, M., Fisher, K., Chen, N., Rieckmann and Cheng, Q. (2004) Sulfadoxine resistance in Plasmodium vivax is associated with a DHPS sequence polymorphism altering the putative drug-binding site. Antimicrobial Agents and Chemotherapy 48(6):2214-2222.
Gatton, M.L., Martin, L.B. & Cheng, Q. (2004) The Evolution of Resistance to Sulfadoxine / Pyrimethamine in Plasmodium falciparum parasites. Antimicrob. Agent. Chemother 48(6): 2116-2123.
Gatton, M.L and Cheng, Q (2004) Modelling the development of acquired clinical immunity to Plasmodium falciparum. Infection and Immunity 72(11),6538-6545.
Chen, N., Wilson, D., Pasay, C.M., Bell, D., Martin, L., Kyle, D. and Cheng, Q. (2005) The origin and dissemination of novel mutant Pfcrt allelic Types of Plasmodium falciparum in the Philippines. Antimicrob. Agent. Chemother 49(5): 2102-2105.
Baker, J., McCarthy, J., Gatton, M.L., Kyle, D., Belizario, V., Luchavez, J., Bell D and Cheng, Q. (2005) Genetic Diversity of Plasmodium falciparum Histidine-Rich Protein 2 and Its Effect on the Performance of PfHRP2-Based Rapid Diagnostic Tests. J. Infect. Dis 192:870-877.
Imwong, M., Pukrittayakamee, S., Cheng, Q., Moore, C., Looareesuwan, S., Snounou, G., White, N.J. and Day, N.P.J. (2005). Limited polymorphism in the dihydropteroate synthetase gene (dhps) of Plasmodium vivax isolates from Thailand. Antimicrob. Agent. Chemother 49(10):4393-4395.
Gatton, M.L., Peters, J.M, Gresty, K., Fowler, E.V., Chen, N. & Cheng Q. (2006) Detection sensitivity and quantitation of Plasmodium falciparum var gene transcripts by real-time RT-PCR in comparison with conventional RT-PCR. Am. J. Trop. Med. Hyg 75(2):212-218.
Fowler, E.V., Chavchich, M., Chen, N., Peters, J.M., Kyle, D., Gatton, M.L and Cheng, Q. (2006) Physical linkage to drug resistance genes results in conservation of var genes among West Pacific Plasmodium falciparum isolates. J. Infect. Dis 194:939-948.
Gatton, M.L and Cheng, Q. (2006) Plasmodium falciparum infection dynamics and transmission potential following treatment with sulfadoxine-pyrimethamine. J. Antimicrob. Chemother 58(1):47-51.
Lee, N., Baker, J., Andrews, K., Gatton, M., Bell, D., Cheng, Q. and McCarthy, J. (2006) The effect of sequence variation in Plasmodium falciparum Histidine-Rich Protein 2 on the binding of specific monoclonal antibodies: implications for Rapid Diagnostic Tests for malaria. J. Clin. Microb 44(8):2773-2778.
Auliff, A., Wilson, D., Russell, B., Gao, Q., Chen, N., Anh, L.N., Maguire, J., O'Neil, M. and Cheng, Q. (2006) Amino acid mutations in Plasmodium vivax DHFR and DHPS from several geographical rerions and susceptibility to antifolate drugs. Am. J. Trop. Med. Hyg 75(4): 617-621.
Lee, N., Baker, J., Bell, D., McCarthy, J. and Cheng, Q. Assessing the genetic diversity of Plasmodium falciparum and Plasmodium vivax aldolases and its potential effect on the performance of Aldolase-based Rapid Diagnostic Tests (RDTs). J Clin Microb 44(12): 4547-4549.
Jennifer M. Peters, Elizabeth V. Fowler, Darren Krause, Nanhua Chen, Qin Cheng, Michelle L. Gatton (2007) Differential changes in Plasmodium falciparum var transcription during adaptation to culture. J. Infect. Dis. 195:748-755.
Chen, N., Auliff, A., , Rieckmann, K., Gatton, L.M. and Cheng, Q. (2007) Relapses of Plasmodium vivax infection result from clonal hypnozoites activated at predetermined intervals. J. Infect. Dis 195(7):934-941.
O'Neil, M.T., Korsinczky, M.L.J, Gresty, K., Auliff, A. and Cheng Q. (2007) A novel P. falciparum expression system for assessing antifolate resistance caused by mutant P. vivax dihydrofolate reductase-thymidylate synthase. J. Infect. Dis. 196:467-474.
Baker, J., McCarthy, J., Gatton, M., Lee, N., Bell, D., Peters, J., Cheng, Q. (2007) Rapid diagnostic tests for malaria: are they sufficiently reliable? ADF Health 8:12-17.
Russell B, Suwanarusk R, Chavchich M, Chalfein F, Kenangalem E, Kosaisavee V, Prasetyorini B, Piera KA, Barends M, Brockman A, Lek-Uthai U, Anstey NM, Tjitra E, Nosten N, Cheng Q and Price RN. (2007) Chloroquine resistant Plasmodium vivax: in vitro characterisation and association with molecular polymorphisms. PLOs One 10,e1089.
Krause, D., Gatton, M.L., Frankland, S., Eisen, D.P., Good, M.F. Lilley, L. and Cheng, Q. (2007) Characterisation of the antibody response against Plasmodium falciparum erythrocyte membrane protein-1 in human volunteers. Infect. Immun. 75(12): 5967-5973.
Chen N, Gao Q, Wang SQ, Wang GZ, Gatton M and Cheng Q. (2008) No genetic bottle-neck in Plasmodium falciparum wild type pfcrt alleles re-emerging in Hainan Island, China following high-level Chloroquine resistance. Antimicrob. Agent. Chemother 52(1): 345-347.
Gatton, ML. and Cheng Q. (2008) Therapeutic efficacy of anti-malarials: parasite diversity, PCR-genotyping and statistics. Trends Parasitol. 24(2):68-73.
Russell B, Chalfien F, Prasetyorini B, Kenangalem E, Piera K, Suwanarusk R, Brockman A, Prayoga, Sugiarto P, Cheng Q, Tjitra E, Anstey NM, Price RN (2008) Determinates of in vitro drug susceptibility testing of Plasmodium vivax. Antimicrob. Agent. Chemother 52(3): 1040-1045.
Hawkins VN, Auliff A, Prajapati S, Rungsihirunrat K, Hapuarachchi C, Maestre A, O'Neil MT, Cheng Q, Joshi H, Na-Bangchang K and Sibley CH. (2008) Multiple origins of resistance-conferring mutations in Plasmodium vivax dihydrofolate reductase. Malaria J (in press)