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

The main parasite that causes malaria, Plasmodium falciparum, continuously evolve to survive drugs used for malaria treatment and prevention. This is already affecting treatment with the most recent drug combinations in South East Asia and there are fears that the same phenomenon may occur in Africa, where millions of people are infected every year and will be at risk of death if currents drugs become less effective. Already, we have seen signs in the genetic material of P. falciparum from across Africa that raises the possibility that drug resistance will occur as we continue to fight malaria with drugs. This project will deploy a new P. falciparum ex-vivo drug survival rate assay, genomic and transcriptomic analysis on field isolates to determine the frequency and mechanisms of tolerance to current antimalaria drugs and selected candidate antimalarial compounds from a library provided by the medicine for malaria venture (MMV). We hypothesize that P. falciparum isolates from low transmission regions of The Gambia and Senegal will be less susceptible to drugs than those from high transmission regions of Ghana and Nigeria and that drug tolerant field isolates will share common molecular markers. Our specific aims are to: (1) determine how P. falciparum antimalarial ex-vivo survival rates vary by transmission intensity and past treatment-based interventions (2) assess the sensitivity of isolates with known genetic markers of resistance to current and candidate antimalarial drugs (3) identify genomic and transcriptomic correlates of ex-vivo drug tolerance (4) assess the temporal and spatial dynamics of genetic variants in known and emerging selective signatures in P. falciparum. We will build on the ongoing collaboration between members of the West African Network for Tuberculosis, AIDS and Malaria (WANETAM) and Plasmodium Diversity Network Africa (PDNA) to enable capacity building in ex-vivo antimalarial sensitivity testing and genomic analysis. Our mission is to train at least 5 MSc students and one PhD student in these approaches. We will also directly supervise an early postdoctoral scientist while giving the opportunity of collaborating PhD students to gain exposure in molecular cell biology and genomics of malaria at our facilities at the Medical Research Council Unit The Gambia at LSHTM (MRCG-LSHTM). Data generated will be shared with the National Malaria Control programs (NMCPs) to inform strategies for interventions.