Current Organisation

Current Job Title

Biography

Project Title

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

EDCTP Project Call

Senior Fellowship Plus (SFP)

Host Organisation

Project Objectives

Our specific objectives are to: Monitor the ex-vivo survival rates of P. falciparum from symptomatic and asymptomatic individuals to different drug combinations. We will identify survival outliers and compare their prevalence between geographic and temporal populations, with transmission and drug intervention variance. The data will be shared with NMCPs that will be involved in providing samples from treatment efficacy studies. Characterise genetic polymorphisms and transcript variation between high vs low tolerance outlier isolates against current and candidate drugs. Innovative machine learning algorithms will be used to identify genetic markers and molecular pathways associated with these phenotypes. Assess the variance in allele frequencies of confirmed and candidate P. falciparum resistance gene panels including; a) MDR1, CRT, Plasmepsin I, Plasmepsin II, Coronin, Atpase1, Ap2G2, Ap2Mu and Kelch13 genes b) An enlarged panel of unvalidated genes in haeme activation of artemisinin; OAT, PyrK, LDH, SpdSyn, SAMS and TCTP that directly bind artemisinin (11). Population analyses of these markers against the history of different drug interventions will elucidate their dynamics and interactions across parasite subpopulations and transmission ecosystems. Determine the flow of local haplotypes of drug tolerance-associated loci between low and high transmission areas. It is often thought that modest/high transmission regions seed infections to low transmission regions but the flow could be in both directions. We will map this flux and the density between study sites and provide this information to the NMCPs to allow them strategise interventions such as SMC.

Project Summary

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.