1. What is the molecular and biochemical basis of parasite resistance to drugs in clinical use and those at an advanced stage of the developmental pipeline?
    2. Does the genetic diversity of malaria parasites within an individual host influence the evolution of parasite virulence and drug resistance?
    3. Does the scaling up of malaria control interventions result in noticeable genetic changes in the parasite population?
  • Understanding drug resistance mechanisms is essential for developing resistance surveillance tools, and for optimising drug deployment. There is global concern about the emergence and spread of malaria parasite resistance to ACTs in Asia. Mass Drug Administration (MDA) with ACTs is both considered a resistance containment strategy in Asia and a transmission reduction strategy within Africa despite concern that MDA will increase drug pressure and may select for resistance. In addition, MDA and other transmission reduction strategies will leave a significant imprint on the parasite genome. Our group at MLW is well positioned to become a global leader in understanding drug resistance mechanisms and parasite evolution within large-scale transmission reduction programmes, thanks to a well-defined heterogeneous malaria burden in the field site in Chikhwawa, low grade transmission in Blantyre, and excellent laboratory facilities at MLW and partner institutes. Chikhwawa is also heavily burdened by other parasites including schistosomes and trypanosomes – which have been understudied in the past but are important causes of morbidity and mortality.
    1. a. To investigate whether or not malaria parasites are developing tolerance and resistance to artemisinin drugs using in vitro and in vivo drug efficacy studies.
      b. To measure the prevalence and fitness costs of the kelch propeller mutations associated with emerging artemisinin and ACT resistance in South East Asia.
      c. To perform genome-wide association studies on drug-selected lines to identify genetic polymorphisms associated with parasite resistance to new drugs at an advanced stage of the developmental pipeline, and those in clinical use.
    2. a.To investigate how accurately a single peripheral blood sample captures all parasite haplotypes present in a malaria infection.
      b. To determine whether the number and relatedness of parasite haplotypes within infections is associated with parasite virulence.
    3. a.To develop and validate a population genetics approach for measuring changes in malaria transmission intensity following enhanced intervention.
      b. To evaluate the impact of scaling up malaria control interventions on parasite genetic structure.
  • £50k with Harold Ochola and Anja Terlouw (MCDC); £450k (main grant support from WT since 2013); recent popln genetics paper - Acta Trop 2015;142:108–114