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Extensive genetic diversity in the Plasmodium falciparum Na+/H+ exchanger 1 transporter protein implicated in quinine resistance.

ABSTRACT: The Plasmodium falciparum Na(+)/H(+) exchanger (Pfnhe-1) locus at chromosome 13 and another locus at chromosome 9 have recently been proposed to influence quinine resistance. Here, we sequenced the ms4760 locus of the Pfnhe-1 gene from 244 P. falciparum isolates collected from five different regions of India. A total of 16 different ms4760 alleles (with one to five DNNND repeats) were observed among these isolates. Interestingly, areas with a high prevalence of chloroquine and sulfadoxine-pyrimethamine resistance showed more Pfnhe-1 DNNND repeats compared to low drug resistance areas. The extent of genetic diversity at the ms4760 locus also varied from one region to another, with expected heterozygosity values ranging from 0.47 to 0.88.

SUBMITTER: Vinayak S

PROVIDER: S-EPMC2167966 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Extensive genetic diversity in the Plasmodium falciparum Na+/H+ exchanger 1 transporter protein implicated in quinine resistance.

Vinayak Sumiti S Alam Mohammad Tauqeer MT Upadhyay Mala M Das Manoj K MK Dev Vas V Singh Neeru N Dash Aditya P AP Sharma Yagya D YD

Antimicrobial agents and chemotherapy 20071008 12

The Plasmodium falciparum Na(+)/H(+) exchanger (Pfnhe-1) locus at chromosome 13 and another locus at chromosome 9 have recently been proposed to influence quinine resistance. Here, we sequenced the ms4760 locus of the Pfnhe-1 gene from 244 P. falciparum isolates collected from five different regions of India. A total of 16 different ms4760 alleles (with one to five DNNND repeats) were observed among these isolates. Interestingly, areas with a high prevalence of chloroquine and sulfadoxine-pyrime ...[more]

PMID: 17923493

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Project description:BACKGROUND: Quinine is still recommended as an effective therapy for severe cases of Plasmodium falciparum malaria, but the parasite has developed resistance to the drug in some cases. Investigations into the genetic basis for quinine resistance (QNR) suggest that QNR is complex and involves several genes, with either an additive or a pairwise effect. The results obtained when assessing one of these genes, the plasmodial Na+/H+ exchanger, Pfnhe-1, were found to depend upon the geographic origin of the parasite strain. Most of the associations identified have been made in Asian strains; in contrast, in African strains, the influence of Pfnhe on QNR is not apparent. However, a recent study carried out in Kenya did show a significant association between a Pfnhe polymorphism and QNR. As genetic differences may exist across the African continent, more field data are needed to determine if this association exists in other African regions. In the present study, association between Pfnhe and QNR is investigated in a series of isolates from central Africa. METHODS: The sequence analysis of the polymorphisms at the Pfnhe-1 ms4760 microsatellite and the evaluation of in vitro quinine susceptibility (by isotopic assay) were conducted in 74 P. falciparum isolates from the Republic of Congo. RESULTS: Polymorphisms in the number of DNNND or NHNDNHNNDDD repeats in the Pfnhe-1 ms4760 microsatellite were not associated with quinine susceptibility. CONCLUSIONS: The polymorphism in the microsatellite ms4760 in Pfnhe-1 that cannot be used to monitor quinine response in the regions of the Republic of Congo, where the isolates came from. This finding suggests that there exists a genetic background associated with geographic area for the association that will prevent the use of Pfnhe as a molecular marker for QNR. The contribution of Pfnhe to the in vitro response to quinine remains to be assessed in other regions, including in countries with different levels of drug pressure.

Project description:The emergence and spread of drug-resistant Plasmodium falciparum impedes global efforts to control and eliminate malaria. For decades, treatment of malaria has relied on chloroquine (CQ), a safe and affordable 4-aminoquinoline that was highly effective against intra-erythrocytic asexual blood-stage parasites, until resistance arose in Southeast Asia and South America and spread worldwide1. Clinical resistance to the chemically related current first-line combination drug piperaquine (PPQ) has now emerged regionally, reducing its efficacy2. Resistance to CQ and PPQ has been associated with distinct sets of point mutations in the P. falciparum CQ-resistance transporter PfCRT, a 49-kDa member of the drug/metabolite transporter superfamily that traverses the membrane of the acidic digestive vacuole of the parasite3-9. Here we present the structure, at 3.2 Å resolution, of the PfCRT isoform of CQ-resistant, PPQ-sensitive South American 7G8 parasites, using single-particle cryo-electron microscopy and antigen-binding fragment technology. Mutations that contribute to CQ and PPQ resistance localize primarily to moderately conserved sites on distinct helices that line a central negatively charged cavity, indicating that this cavity is the principal site of interaction with the positively charged CQ and PPQ. Binding and transport studies reveal that the 7G8 isoform binds both drugs with comparable affinities, and that these drugs are mutually competitive. The 7G8 isoform transports CQ in a membrane potential- and pH-dependent manner, consistent with an active efflux mechanism that drives CQ resistance5, but does not transport PPQ. Functional studies on the newly emerging PfCRT F145I and C350R mutations, associated with decreased PPQ susceptibility in Asia and South America, respectively6,9, reveal their ability to mediate PPQ transport in 7G8 variant proteins and to confer resistance in gene-edited parasites. Structural, functional and in silico analyses suggest that distinct mechanistic features mediate the resistance to CQ and PPQ in PfCRT variants. These data provide atomic-level insights into the molecular mechanism of this key mediator of antimalarial treatment failures.

Dataset Information

Extensive genetic diversity in the Plasmodium falciparum Na+/H+ exchanger 1 transporter protein implicated in quinine resistance.

Publications

Extensive genetic diversity in the Plasmodium falciparum Na+/H+ exchanger 1 transporter protein implicated in quinine resistance.

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