: The development and spread of drug resistance in malaria parasites has become a major obstacle in the treatment and control of the disease that causes approximately 300 million infections and up to 3 million deaths per-year. A better understanding of factors that influence the emergence and survival of drug resistant parasites will help develop intervention strategies that minimize the risk of drug resistance and prolong the effective life of anti-malarial drugs. The ability for P. falciparum parasites to vary the surface protein, PfEMP1, antigenically is important for immune evasion and pathogenesis. PfEMP1, which is encoded by the var genes, allows the parasitized cells to adhere to the linings of blood vessels thereby avoiding destruction by the spleen. PfEMP1 also stimulates a host specific antibody response that kills parasites expressing the protein, while parasites that have switched to express a different variant survive. We hypothesize that antigenic variation of PfEMP1 also plays an important role in the survival and spread of drug resistant malaria parasites. This proposal aims to investigate the process involved in PfEMP1 antigenic variation, the switch rates of these antigens, and the role that PfEMP1 switching and the corresponding host anti-PfEMP1 responses play in the emergence, evolution, maintenance and spread of drug resistance in Plasmodium falciparum. We will use experimental procedures and mathematical simulation models to investigate: 1) Investigate antigenic variation and its role in parasite survival by examining the var gene switching process and associated switch rates in P. falciparum parasites from ex vivo samples of defined strains and from various regions of the world. 2) Investigate the transcribed var genes in parasite populations of pre-treatment and post-treatment recrudescence's to provide experimental proof for the role of antigenic switching in the survival of drug resistant parasites causing treatment failures. 3) Investigate the role of PfEMP1 in determining the parasite population and spread of drug resistance by examining the linkage between PfEMP1 and drug resistance markers in field isolates. 4) Investigate the importance of factors such as antigenic variation, parasite diversity and treatment strategies for the establishment and spread of drug resistant parasite populations within communities, by modeling in-host dynamics and transmission. The outcome of this research will help to develop intervention strategies that minimize the risk of drug resistance and prolong the effective life of anti-malarial drugs. The project has the potential to benefit the health of a substantial proportion of the world's population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047500-06
Application #
7082864
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Coyne, Philip Edward
Project Start
1999-09-30
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
6
Fiscal Year
2006
Total Cost
$184,559
Indirect Cost
Name
Queensland Institute of Medical Research
Department
Type
DUNS #
758815328
City
Herston
State
Country
Australia
Zip Code
4006
Gatton, Michelle L; Cheng, Qin (2010) Interrupting malaria transmission: quantifying the impact of interventions in regions of low to moderate transmission. PLoS One 5:e15149
Gatton, Michelle L; Cheng, Qin (2008) Can estimates of antimalarial efficacy from field studies be improved? Trends Parasitol 24:68-73
Chen, Nanhua; Gao, Qi; Wang, Shanqing et al. (2008) No genetic bottleneck in Plasmodium falciparum wild-type Pfcrt alleles reemerging in Hainan Island, China, following high-level chloroquine resistance. Antimicrob Agents Chemother 52:345-7
Krause, Darren R; Gatton, Michelle L; Frankland, Sarah et al. (2007) Characterization of the antibody response against Plasmodium falciparum erythrocyte membrane protein 1 in human volunteers. Infect Immun 75:5967-73
Peters, Jennifer M; Fowler, Elizabeth V; Krause, Darren R et al. (2007) Differential changes in Plasmodium falciparum var transcription during adaptation to culture. J Infect Dis 195:748-55
Gatton, Michelle L; Peters, Jennifer M; Gresty, Karryn et al. (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 75:212-8
Gatton, Michelle L; Cheng, Qin (2006) Plasmodium falciparum infection dynamics and transmission potential following treatment with sulfadoxine-pyrimethamine. J Antimicrob Chemother 58:47-51
Fowler, Elizabeth V; Chavchich, Marina; Chen, Nanhua et al. (2006) Physical linkage to drug resistance genes results in conservation of var genes among West Pacific Plasmodium falciparum isolates. J Infect Dis 194:939-48
Gatton, Michelle L; Martin, Laura B; Cheng, Qin (2004) Evolution of resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum. Antimicrob Agents Chemother 48:2116-23
Gatton, M L; Cheng, Q (2004) Investigating antigenic variation and other parasite-host interactions in Plasmodium falciparum infections in naive hosts. Parasitology 128:367-76

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