Plasmodium falciparum anti-malarial drug resistance in The Gambia: Identification of potential genetic markers by retrospective whole genome approaches
The main goal of this proposal is to identify and determine the distribution of drug-resistant markers in a West African population, The Gambia, following five years of implementation of ACT. In the past few years molecular methods have been developed, to study genetics, population genomic diversity, and evolution of malaria parasites in West Africa.
The specific aims are to:
- Characterize variation in microsatellite and single nucleotide polymorphisms in malaria infections following the implementation of ACT in The Gambia,
- Determine the prevalence of resistance markers in endemic communities and
- Determine the association of these polymorphisms with treatment failure and reduce drug sensitivity.
The study will employ hybrid-select and Illumina sequencing of retrospective isolates in collaboration with the Broad Institute, US. High resolution drug sensitivity phenotyping of field isolates will employ new flow cytometric techniques that allow determination of the effects of artemisinin derivatives on early developmental stages of parasites. The genomes of parasites from ex vivo and in vivo studies will be genotyped in collaboration with the Wellcome Trust Sanger institute, UK.
The project will be of public health benefit in identifying and combating drug-resistant malaria, potentially enhancing the drive towards malaria elimination in the Gambia. The genomic data will be vital in studies charaterising malaria diversity.
Malaria disease from infection with the parasite Plasmodium falciparum remains an important global health problem. More information is needed to continue developing new ways of controlling the disease which infects predominantly impoverished endemic countries in sub Saharan Africa. Some of this includes information on genetic differences between different types of the parasites, particularly those that don't respond to the drugs presently used for treatment.
Malaria has developed resistance to previously available cheap drugs like chloroquine and pyrimethanil. Due to this strong ability to develop new ways of evading drugs and continuing transmission of infection and cause disease in other individuals, it now requires the use of new drug combinations containing the compound artemisinin (ART) to treat infections. These new drug combinations (ACTs) are more expensive and represent the only most effective treatment of malaria infections in sub saharan Africa. However, there are indications that some infections with malaria in South East Asia are not treated as effectively as expected with these new drug combinations indicating that the parasites may already be developing new mechanisms to resist the effect of these drug combinations. If this alarming development were to continue and spread to Africa it will be a big blow to the efforts to reduce the burden of malaria in the continent that bears 90% of the malaria burden.
For the scientific community to be ready for such an eventuality, it is important to start looking at factors that will enable these parasites that resist drug action to develop and spread in affected sub Saharan Arican populations. Some of these factors include the ability of some parasites to tolerate drug concentrations that will normally kill them. The challenge in gaining understanding of the complex processes in the parasite that create the conditions for drug resistance is the requirement for large amount of data from populations where these drugs have been used for some time. Acquiring such information can now be possible by advancements in technologies for rapidly analysing the quantity and quality of genetic differences between infections before and since ACT adoption in Africa.
This project therefore seeks a better understanding of the processes that lead to antimalarial drug resistance by taking advantage of advances in new technologies to comprehensively study genetic differences in the parasites from the period before ACTs through five years of its use in the West African state, The Gambia. Use of drugs and the low level of transmission in this region is favorable for parasites to develop resistance. This information will enable the identification of genetic determinants of drug resistance and communities in which parasites that do not respond to drugs are transmitted. The study will then employ methods in the lab to determine the sensitivity of these parasites to the drugs being used. Those that are resistant to drugs will be analysed using genetics tools.
The study will also look at how parasites will be cleared from infected people being treated with ACTs. Communities with parasites that fail to clear from blood during treatment will be the focus of further genetic analysis to determine if genetic changes are responsible for this kind of behaviour. This project will make use of excellent collaboration between MRC Unit, The Gambia and Northern partners (UK and US) for analysis and technology transfer. The study will last for a period of 48 months and will build capacity for future population genetic research in the African sub-region given the different vaccine, drug and vector interventions being implemented.
The findings from the project should also inform policymakers on developing new intervention strategies that will incorporate the peculiarities of populations studied.