Malaria parasite population structure and adaptation on the edge of endemic distribution in Africa

We aim to know how to better control malaria in one of the most disadvantaged populations of the world. There is very little medical research conducted in Mauritania, in the north western part of sub-Saharan Africa, but the information we have indicates that malaria is a problem throughout the south of the country where most of the population live - most of the north of the country is Saharan desert. However, the disease could probably be effectively controlled and possibly even eliminated in the long-term with appropriate efforts. In countries immediately to the south, particularly in The Gambia and Senegal, recent scale up of interventions has coincided with a significant decline in malaria. Although control in Mauritania may have lagged behind it is in a situation with only a short season of mosquito transmission where the parasites might be eliminated given the right approach. The investigating team at the London School of Hygiene and Tropical Medicine and the National Institute of Public Health Research in Mauritania are planning to use state of the art genomics and cell culture methods along with collaborators at Harvard University and the Wellcome Trust Sanger Institute in the UK as well as in neighbouring Senegal, to understand the parasite populations and how they adapt to antimalarial drugs and invade red cells in a population where most people have little immunity to the infection. This understanding may help target interventions to particular parts of Mauritania and also help in the design of a vaccine that could induce immunity against the stage of the parasite that invades red cells.

Appropriate development of antimalarial vaccines and drugs needs to be informed by an understanding of processes of adaptation of malaria parasites in endemic populations. We will investigate population genetic structure and phenotypes of P. falciparum under selection at the north western extreme of its African range in Mauritania where endemicity persists despite limited and highly seasonal rainfall that restricts transmission. We predict that, compared with countries to the south that we recently studied, genetic divergence between populations of P. falciparum in different areas of Mauritania will be high due to genetic drift with small effective population sizes, and restricted gene flow among endemic foci. This will be investigated by conventional microsatellite analyses and whole genome sequence polymorphism analyses. We also predict that the selective landscape will be strikingly different from elsewhere, leading to measurable effects including the following: (i) a low level of acquired immunity in the human population will reduce diversifying selection on merozoite invasion ligands so these will be less diverse and highly skewed towards the use of a particular preferred primary ligand, which we can test with precision using a new erythrocyte culture and receptor knockdown system; (ii) alleles under strong positive selection will increase to high frequencies in local populations before sporadic gene flow events allow them to spread so there will be major local differences in drug resistance. Understanding these processes in terms of demographic and selective constraints on the parasite will guide targeting of existing control tools including antimalarial drugs and development of new tools including vaccines.