Plasmodium falciparum tolerance to antimalarial drugs in West Africa: Molecular Determinants and Evolutionary Dynamics (Emerging Genomic Selection and AntiMalarial Tolerance in African – EGSAT) (EGSAT)

The vision of this project is to train leaders in malaria cell biology and genomics, to determine and evaluate the efficacy of current and future antimalarial drugs, and the evolutionary dynamics imposed by multiple concurrent treatments of individuals and communities.

Antimalarial drugs impose the strongest selective force on malaria parasites and we have detected recent signatures of directional selection in genes associated with delayed or failed ACT treatment in Africa.

Several concurrent antimalarial combinations are now used for clinical treatment or community interventions such as seasonal malaria chemoprevention (SMC).

For example, the Gambia like other sahel countries applies SMC with sulphadoxine-pyrimethamine (SP) plus amodiaquine while recommending Artemether Lumefantrine (AL) as firstline ACT.

Some populations have also been subjected, in the last 4-years, to mass drug administration of Didydroartemisin-Piperaquine (DHPQ) alone or in combination with Ivermectin while SP is continuously administered for malaria prevention in pregnancy.

These multiple drug pressures could drive (multiple drug) resistance development and a return to the previous rates of high malaria burden and mortality.

We hypothesise that P. falciparum isolates from low transmission regions of Gambia and Senegal will be more tolerant to antimalarials than those from high transmission Ghana and Nigeria and this will be determined by common molecular variants.

The overall scientific goal of this project is therefore to determine the role of emerging and re-emerging genomics signatures of directional selection in antimalarial drug susceptibility, tolerance and resistance.

This project will deploy new P. falciparum ex-vivo drug survival rate assay, genomic and transcriptomic analyses to determine the frequency and mechanisms of P. falciparum tolerance to current ACT drugs and selected MMV candidate antimalarial compounds.

Our specific aims will be: (1) to determine how P. falciparum antimalarial ex-vivo survival rates vary by transmission intensity and history of chemoprevention (2) assess the sensitivity of isolates with known genetic markers of resistance to current and candidate antimalarial drugs (3) to identify genomic and transcriptomic correlates of ex-vivo drug tolerance (4) to assess the temporal and spatial dynamics of genetic variants in known and emerging selective signatures in P. falciparum.

We will build on an ongoing collaboration between members of the West African Network for Tuberculosis, AIDS and Malaria (WANETAM) and Pan-African Malaria Genetic EPidemiology (PEMGENe) to enable capacity building in ex-vivo antimalarial sensitivity testing and genomic analysis. Data generated will be shared with the National malaria control programmes to inform strategies for interventions.