Summary
This project investigates compensatory mutations in Plasmodium falciparum that evolve to restore fitness after drug resistance mutations, using reverse genetic approaches, modified in vitro drug selection, and longitudinal field evolution monitoring.
What they want
The project will use three complementary approaches to investigate compensation in Plasmodium falciparum. First, reverse genetic approaches will be used to investigate the role of the amino acid transporter pfaat1 in quinolone drug resistance evolution, testing if mutations in this locus compensate for reduced fitness of CQ-resistant parasites or play a role in response to other quinolone drugs. Second, a modified in vitro drug selection approach will be used to identify compensatory loci by introducing known resistance mutations onto a drug-sensitive background and culturing parasites in the absence of drug pressure to select for fitness-restoring mutations, specifically targeting compensation for pfcrt mutations (piperaquine resistance) and kelch13 mutations (artemisinin resistance). Third, the project will examine genes showing similar patterns of allele frequency change to kelch13 on the Thai-Myanmar border to identify compensatory loci, hypothesizing enrichment for genes involved in compensatory roles.
Deliverables
- Investigation of pfaat1's role in quinolone drug resistance evolution
- Identification of mutations and biochemical pathways that compensate for pfcrt and kelch13 mutations
- Examination of genes showing parallel allele frequency changes to kelch13 on the Thai-Myanmar border
Technical requirements
- Reverse genetic approaches
- Genetic mapping methods (e.g., linkage mapping, genome wide association)
- Modified in vitro drug selection
- Monitoring longitudinal evolution within parasite populations
