Sequence-based association and selection scans identify drug resistance loci in the
            <i>Plasmodium falciparum</i>
            malaria parasite

Park, Daniel J.; Lukens, Amanda K.; Neafsey, Daniel E.; Schaffner, Stephen F.; Chang, Hsie-Chia; Valim, Clarissa; Ribacke, Ulf; Tyne, Daria Van; Galinsky, Kevin; Galligan, Meghan; Becker, Justin S.; Ndiaye, Daouda; Mboup, Souleymane; Wiegand, Roger C.; Hartl, Daniel L.; Sabeti, Pardis C.; Wirth, Dyann F.; Volkman, Sarah K.

doi:10.1073/pnas.1210585109

Cited by 108 publications

(100 citation statements)

References 46 publications

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“…To gain insight into the mechanism of action of (+)-SJ733 and the potential for acquisition of resistance, we selected drug-resistant mutant strains of P. falciparum in vitro and P. berghei in vivo, using (+)-SJ733 and other DHIQ analogs, and characterized the alleles conferring resistance (6,10). Mutant strains were generated in vitro by pressuring erythrocytic cocultures with (+)-SJ733 or other DHIQ analogs (SI Appendix, SI Materials and Methods) until apparently resistant parasites emerged.…”

Section: Significancementioning

confidence: 99%

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

Jiménez-Dı́az

Ebert

Salinas

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

217

291

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Significance Useful antimalarial drugs must be rapidly acting, highly efficacious, and have low potential for developing resistance. (+)-SJ733 targets a Plasmodium cation-transporting ATPase, ATP4. (+)-SJ733 cleared parasites in vivo as quickly as artesunate by specifically inducing eryptosis/senescence in infected, treated erythrocytes. Although in vitro selection of pfatp4 mutants with (+)-SJ733 proceeded with moderate frequency, during in vivo selection of pbatp4 mutants, resistance emerged slowly and produced marginally resistant mutants with poor fitness. In addition, (+)-SJ733 met all other criteria for a clinical candidate, including high oral bioavailability, a high safety margin, and transmission blocking activity. These results demonstrate that targeting ATP4 has great potential to deliver useful drugs for malaria eradication.

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Section: Significancementioning

confidence: 99%

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

Jiménez-Dı́az

Ebert

Salinas

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

217

291

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“…Evidence for the importance of transcriptional regulation to the success of P. vivax was found both by haplotype-based and allele frequency-based tests of selection. Although known and putative drug-resistance genes were found at the center of selective sweeps in both P. falciparum and P. vivax in this and other studies (Tables 2 and 3), the strongest selective sweep in the P. vivax population occurred in close proximity to an AP2 transcription factor (PVX_122680), suggesting that P. vivax is responding to selective pressures by altering its transcriptional profile (29,34,35).…”

Section: Discussionmentioning

confidence: 80%

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Parobek

Lin

Saunders

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cambodia, in which both Plasmodium vivax and Plasmodium falciparum are endemic, has been the focus of numerous malaria-control interventions, resulting in a marked decline in overall malaria incidence. Despite this decline, the number of P. vivax cases has actually increased. To understand better the factors underlying this resilience, we compared the genetic responses of the two species to recent selective pressures. We sequenced and studied the genomes of 70 P. vivax and 80 P. falciparum isolates collected between 2009 and 2013. We found that although P. falciparum has undergone population fracturing, the coendemic P. vivax population has grown undisrupted, resulting in a larger effective population size, no discernable population structure, and frequent multiclonal infections. Signatures of selection suggest recent, species-specific evolutionary differences. Particularly, in contrast to P. falciparum, P. vivax transcription factors, chromatin modifiers, and histone deacetylases have undergone strong directional selection, including a particularly strong selective sweep at an AP2 transcription factor. Together, our findings point to different population-level adaptive mechanisms used by P. vivax and P. falciparum parasites. Although population substructuring in P. falciparum has resulted in clonal outgrowths of resistant parasites, P. vivax may use a nuanced transcriptional regulatory approach to population maintenance, enabling it to preserve a larger, more diverse population better suited to facing selective threats. We conclude that transcriptional control may underlie P. vivax's resilience to malaria control measures. Novel strategies to target such processes are likely required to eradicate P. vivax and achieve malaria elimination.D uring the last decade, western Cambodia has been the focus of numerous and multimodal interventions to control the spread of artemisinin-resistant Plasmodium falciparum (1, 2). Such interventions, including increased vector control, increased surveillance, and improved access to quality artemisinin-combination therapy (ACT), would be expected to curtail coendemic Plasmodium vivax as well. However, even as P. falciparum infections in Cambodia decreased by 81% between 2009 and 2013, P. vivax cases have increased, making it the predominant species in the Mekong region (3-6). This scenario, repeated in Brazil and other areas of coendemicity, has led to growing awareness that P. vivax, although infecting the same populations and transmitted by the same mosquito vectors, will likely be the more challenging species to eradicate (6-9). In this study, we use population genomics to gain insight into the evolutionary factors underlying P. vivax's resilience to malaria control measures.Population genetic studies have previously hinted at the resilience of P. vivax populations in comparison with P. falciparum. Studies of microsatellites and highly variable antigens of sympatric P. vivax and P. falciparum populations in Southeast Asia and the Southwest Pacific have consistently shown P. viv...

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“…Drug data from Senegalese parasites (see Fig. 2 for a summary) were generated with a high-throughput SYBR green I-based assay and have been previously reported (13). In all cases, IC 50 s were calculated with GraphPad Prism (GraphPad, San Diego, CA) by using a four-parameter, log-logistic nonlinear regression of fluorescence intensity versus log 10 -transformed drug concentrations.…”

Section: Methodsmentioning

confidence: 99%

“…Whole-genome sequencing of 45 culture-adapted parasite lines from Senegal was conducted, and genomewide association studies were performed previously (13). The SNP Pf_10_001435509 (by PlasmoDB v5.0 coordinates; also known as Pf_10_001434265 in PlasmoDB v5.5-v7.2 and Pf_10_001434268 in PlasmoDB v9.1) encodes a cysteine-to-serine point mutation at position 591 within the SPAM domain of MSPDBL2.…”

Section: Methodsmentioning

confidence: 99%

Modulation of PF10_0355 (MSPDBL2) Alters Plasmodium falciparum Response to Antimalarial Drugs

Tyne

Uboldi

Healer

et al. 2013

Antimicrob Agents Chemother

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bMalaria's ability to rapidly adapt to new drugs has allowed it to remain one of the most devastating infectious diseases of humans. Understanding and tracking the genetic basis of these adaptations are critical to the success of treatment and intervention strategies. The novel antimalarial resistance locus PF10_0355 (Pfmspdbl2) was previously associated with the parasite response to halofantrine, and functional validation confirmed that overexpression of this gene lowered parasite sensitivity to both halofantrine and the structurally related antimalarials mefloquine and lumefantrine, predominantly through copy number variation. Here we further characterize the role of Pfmspdbl2 in mediating the antimalarial drug response of Plasmodium falciparum. Knockout of Pfmspdbl2 increased parasite sensitivity to halofantrine, mefloquine, and lumefantrine but not to unrelated antimalarials, further suggesting that this gene mediates the parasite response to a specific class of antimalarial drugs. A single nucleotide polymorphism encoding a C591S mutation within Pfmspdbl2 had the strongest association with halofantrine sensitivity and showed a high derived allele frequency among Senegalese parasites. Transgenic parasites expressing the ancestral Pfmspdbl2 allele were more sensitive to halofantrine and structurally related antimalarials than were parasites expressing the derived allele, revealing an allele-specific effect on drug sensitivity in the absence of copy number effects. Finally, growth competition experiments showed that under drug pressure, parasites expressing the derived allele of Pfmspdbl2 outcompeted parasites expressing the ancestral allele within a few generations. Together, these experiments demonstrate that modulation of Pfmspdbl2 affects malaria parasite responses to antimalarial drugs. Malaria drug resistance poses a serious threat to treatment and control efforts (1, 2). Loci such as pfcrt, dhfr, and pfmdr1 are all known to play a role in mediating Plasmodium falciparum drug resistance and can do so through mutations or copy number variation (CNV) (3), but the precise mechanisms of resistance to many antimalarial drugs are poorly understood. Additionally, these well-known loci do not fully explain the range of responses observed in resistant parasites, suggesting that other loci may be involved in mediating parasite drug sensitivity (4, 5).Pfmspdbl2, also called PF10_0355, PF3D7_1036300, and MSP3.8, is a novel antimalarial resistance locus recently identified in a genome-wide association study (GWAS) of 50 global parasite isolates with a high-density single nucleotide polymorphism (SNP) array (6). CNV was also observed at this locus among natural parasite isolates, and parasites with more than one copy of Pfmspdbl2 tended to be more resistant to halofantrine. Overexpression of either the sensitive or the resistant allele of Pfmspdbl2 made parasites less sensitive to halofantrine, mefloquine, and lumefantrine but not to structurally unrelated antimalarials. This validated Pfmspdbl2 as a novel antimalaria...

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Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite

Cited by 108 publications

References 46 publications

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Modulation of PF10_0355 (MSPDBL2) Alters Plasmodium falciparum Response to Antimalarial Drugs

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