The EGSAT project focuses on Plasmodium falciparum tolerance to antimalarial drugs in West Africa: Molecular Determinants and Evolutionary Dynamics.

The four-year project started in 2021 and will end in 2021 with a vision to build leadership 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.

Project rationale

Antimalarial drugs impose the strongest selective force on malaria parasites. In Africa, recent signatures of directional selection in genes associated with delayed or failed ACT treatment have been detected. Several concurrent antimalarial combinations are now used for clinical treatment or community interventions such as seasonal malaria chemoprevention (SMC). The Gambia like other Sahel countries for instance applies SMC with sulphadoxine-pyrimethamine (SP) plus amodiaquine while recommending Artemether Lumefantrine (AL) as first-line ACT. In the last four year, some populations have also been subjected 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.

As such, we hypothesise that Plasmodium falciparum isolates from low transmission regions of The Gambia and Senegal will be more tolerant to antimalarials than those from high transmission Ghana and Nigeria. This will be determined by common molecular variants.

Project objectives

The overall scientific goal of this EGSAT project is to determine the role of emerging and re-emerging genomics signatures of directional selection in antimalarial drug susceptibility, tolerance and resistance. The project will deploy new Plasmodium Falciparum ex-vivo drug survival rate assay, genomic and transcriptomic analyses to determine the frequency and mechanisms of Plasmodium Falciparum tolerance to current ACT drugs and selected MMV candidate antimalarial compounds.

The project’s specific objectives are:

• To determine how Plasmodium Falciparum antimalarial ex-vivo survival rates vary by transmission intensity and history of chemoprevention
• To assess the sensitivity of isolates with known genetic markers of resistance to current and candidate antimalarial drugs
• To identify genomic and transcriptomic correlates of ex-vivo drug tolerance
• To assess the temporal and spatial dynamics of genetic variants in known and emerging selective signatures in Plasmodium Falciparum.

Where we work

• The Gambia, Malaria Population Biology Group, DCE, MRC Unit The Gambia at LSHTM
• Senegal, L’Institut de recherche en santé de surveillance épidémiologique et de formation (IRESSEF), Diamniadio Institute Pasteur de Dakar, Dakar
• Ghana West African Centre for Cell Biology of infectious Pathogens (WACCBIP), University of Ghana, Accra
• Nigeria Nigerian Institute of Medical Research (NIMR), Lagos