Dissecting the loci of low‐level quinine resistance in malaria parasites

Abstract

SummaryQuinine (QN) remains effective against Plasmodium falciparum , but its decreasing efficacy is documented from different continents. Multiple genes are likely to contribute to the evolution of QN resistance. To locate genes contributing to QN response variation, we have searched a P. falciparum genetic cross for quantitative trait loci (QTL). Results identify additive QTL in segments of chromosomes (Chrs) 13, 7 and 5, and pairwise effects from two additional loci of Chrs 9 and 6 that interact, respectively, with the QTL of Chrs 13 and 7. The mapped segments of Chrs 7 and 5 contain pfcrt , the determinant of chloroquine resistance (CQR), and pfmdr1 , a gene known to affect QN responses. Association of pfcrt with a QTL of QN resistance supports anecdotal evidence for an evolutionary relationship between CQR and reduced QN sensitivity. The Chr 13 segment contains several candidate genes, one of which ( pfnhe-1 ) encodes a putative Na + /H + exchanger. A repeat polymorphism in pfnhe-1 shows significant association with low QN response in a collection of P. falciparum strains from Asia, Africa and Central and South America. Dissection of the genes and modifiers involved in QN response will require experimental strategies that can evaluate multiple genes from different chromosomes in combination.

Advances in understanding the genetic basis of antimalarial drug resistance

“…The authors postulate that the PFL1155w amplification may affect SP sensitivity. Ferdig et al [16] mapped the QTL associated with quinine resistance using 35 independent progeny from the cross of quinine low level resistant and sensitive clones. Markers from linkage groups on each of the 14 P. falciparum chromosomes are distributed on the horizontal axis.…”

“…Resistance to quinine, a drug used for over 350 years, exhibits such a phenotype. To explore this, Ferdig et al [16] assessed 35 independent progeny, derived from the cross of a low level quinine resistant and a quinine sensitive clone, for their degree of quinine sensitivity. They then statistically analyzed microsatellite markers from each progeny to map the quantitative trait loci (QTL).…”

Genetic and genomic approaches for the discovery of parasite genes involved in antimalarial drug resistance

“…3), implying that quinine resistance is a multigenic trait (Ferdig et al 2004). QTL mapping revealed contributory loci on five chromosomes, including regions containing Pfmdr1 and Pfcrt on chromosomes 5 and 7, respectively.…”

Étude de la résistance dePlasmodium falciparumaux antipaludiques au sein du réseau international des Instituts Pasteur (RIIP-Palu)

“…Le gène Pfnhe-1 (chromosome 13) code pour une protéine impliquée dans les mécanismes d'homéostasie parasitaire comme la régulation du pH, le volume et la composition ionique du cytoplasme [54]. Il a été en particulier montré que le niveau d'expression de la protéine PfNHE influençait la sensibilité des parasites à la quinine en liaison avec d'autres facteurs, et que certains allèles du microsatellite intragénique ms4760 étaient associés à des diminutions de sensibilité in vitro d'isolats ou de clones de P. falciparum adaptés en culture [55].…”