Biology subjects

Niare, K.

Publications and source records attributed to Niare, K..

4 recordsLinked to original sources

bioRxiv2026

A Plasmodium falciparum PX1 haplotype is associated with reduced susceptibility to artemisinin and lumefantrine

Effective control of falciparum malaria depends on the sustained efficacy of frontline antimalarial drugs, particularly artemether-lumefantrine (AL), the most widely used therapy in Africa. However, the emergence of artemisinin partial resistance and reduced lumefantrine susceptibility in eastern Africa threaten malaria control and elimination. Robust genetic markers of decreased susceptibility to lumefantrine remain elusive, and our understanding of artemisinin resistance is incomplete. We report results of a Plasmodium falciparum genetic cross between a drug-sensitive line and a Ugandan strain exhibiting reduced susceptibility to dihydroartemisinin and lumefantrine. Targeted deep sequencing of progeny pools and 460 recombinant progeny clones derived under drug pressures revealed distinct haplotypic signatures. Drug-selection experiments identified genetic polymorphisms in Plasmodium falciparum px1, encoding a phosphoinositide-binding protein, as the strongest correlates of reduced susceptibility to dihydroartemisinin and lumefantrine. The PX1 PIN haplotype (L1222P, M1701I, D1705N) recently discovered in Ugandan parasites was highly enriched following dihydroartemisinin or lumefantrine treatment of pooled mixtures of genetically diverse Ugandan clinical isolates. This haplotype was associated with reduced susceptibility to dihydroartemisinin and lumefantrine, compared to wild-type sequence, in culture-adapted Ugandan P. falciparum lines. These results confirm that PX1 mutations were selected across geographically distinct Ugandan parasite backgrounds. Long-term competitive fitness assays demonstrated that PX1 mutations confer asexual blood-stage parasites with a growth advantage, potentially explaining a rapid rise of PX1 PIN alleles over the last two decades in Uganda. Overall, our data suggest the PX1 PIN haplotype is a robust marker of reduced AL susceptibility in African P. falciparum, enabling surveillance of emerging drug resistance.

microbiology↗

bioRxiv2025

Geographical variation drives adaptive equilibrium of the P. falciparum sickle-associated mutations

The recent discovery of genetic mutations in Plasmodium falciparum--the most lethal malaria parasite--that enable it to overcome the protective effects of sickle cell trait, raises fundamental questions about the underlying biological and evolutionary interactions. Here we develop a geostatistical model to compare sickle haemoglobin genotype frequencies to the Plasmodium falciparum sickle-associated alleles across global populations, and find a robust association at multiple geographical scales, implying that sickle drives positive selection for these parasite mutations. A model of parasite evolution and an analysis of local haplotype patterns suggest that key features of these mutations - that they are polymorphic in all African populations and are mutually correlated despite lying in different genome regions - are caused by geographical variation in selection pressure, and that the alleles may have been maintained by balancing selection over timescales comparable to the age of the sickle mutation itself. The predicted impact of this host-parasite interaction on disease outcomes varies widely across populations, and functional data are needed to discover the biological mechanisms involved.

genetics↗

bioRxiv2025

A novel locus associated with decreased susceptibility of Plasmodium falciparum to lumefantrine and dihydroartemisinin has emerged and spread in Uganda

Malaria control in Uganda is threatened by the emergence of artemisinin partial resistance and reduced lumefantrine susceptibility. To identify loci contributing to decreased drug susceptibility, we assessed signatures of selection in Ugandan whole-genome Plasmodium falciparum sequences. Extended shared haplotypes were seen for Kelch13 C469Y and A675V mutations, but the strongest signal of recent selection was centered on a segment of chromosome 7 encoding the phosphoinositide-binding protein (PX1, PF3D7_0720700). A haplotype, represented by three PX1 mutations (L1222P, M1701I, D1705N) and two deletions (designated PIN), was first seen in 2008 and rapidly increased, reaching prevalence >50% in northern Uganda by 2016 and eastern Uganda by 2023. PIN-carrying parasites showed significantly decreased ex vivo susceptibilities to lumefantrine, mefloquine and dihydroartemisinin. A parasite strain in which px1 was disrupted in vitro showed increased susceptibility to the three drugs. Thus, PX1 polymorphisms appear to impact on the susceptibilities of African malaria parasites to key drugs.

genomics↗

bioRxiv2024

Population genomics of Plasmodium ovale species in sub-Saharan Africa

Plasmodium ovale curtisi (Poc) and Plasmodium ovale wallikeri (Pow) are relapsing malaria parasites endemic to Africa and Asia that were previously thought to represent a single species. Amid increasing detection of ovale malaria in sub-Saharan Africa, we performed a population genomic study of both species across the continent. We conducted whole-genome sequencing of 25 isolates from Central and East Africa and analyzed them alongside 20 previously published African genomes. Isolates were predominantly monoclonal (43/45), with their genetic similarity aligning with geography. Pow showed lower average nucleotide diversity (1.8x10-4) across the genome compared to Poc (3.0x10-4) (p < 0.0001). Signatures of selective sweeps involving the dihydrofolate reductase gene were found in both species, as were signs of balancing selection at the merozoite surface protein 1 gene. Differences in the nucleotide diversity of Poc and Pow may reflect unique demographic history, even as similar selective forces facilitate their resilience to malaria control interventions.

genomics↗