<i>Plasmodium falciparum</i>
            Gametocytes from Culture in Vitro Develop to Sporozoites That Are Infectious to Primates

Campbell, C. C.; We, Collins; Nguyen-Dinh, Phuc; Barber, Ann; Broderson,

doi:10.1126/science.7051285

Cited by 32 publications

(13 citation statements)

References 20 publications

(13 reference statements)

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“…HB3 is a CQS parasite derived from Honduras. The progenitor of Dd2 was derived from a Laotian patient who failed CQ therapy (Campbell et al ., 1982), and this line also has high‐level resistance to pyrimethamine. Dd2 was cloned from W2‐mef which was selected in the laboratory by mefloquine (MQ).…”

Section: Discussionmentioning

confidence: 99%

Chloroquine susceptibility and reversibility in a Plasmodium falciparum genetic cross

Patel¹,

Drew²,

Tan³

et al. 2010

Molecular Microbiology

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Summary Mutations in the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT), are major determinants of verapamil (VP)-reversible CQ resistance (CQR). In the presence of mutant PfCRT, additional genes contribute to the wide range of CQ susceptibilities observed. It is not known if these genes influence mechanisms of chemosensitization by CQR reversal agents. Using quantitative trait locus (QTL) mapping of progeny clones from the HB3 × Dd2 cross, we show that the P. falciparum multidrug resistance gene 1 (pfmdr1) interacts with the Southeast Asia-derived mutant pfcrt haplotype to modulate CQR levels. A novel chromosome 7 locus is predicted to contribute with the pfcrt and pfmdr1 loci to influence CQR levels. Chemoreversal via a wide range of chemical structures operates through a direct pfcrt-based mechanism. Direct inhibition of parasite growth by these reversal agents is influenced by pfcrt mutations and additional loci. Direct labeling of purified recombinant PfMDR1 protein with a highly specific photoaffinity CQ analogue, and lack of competition for photolabeling by VP, supports our QTL predictions. We find no evidence that pfmdr1 copy number affects CQ response in the progeny, however, inheritance patterns indicate that an allele-specific interaction between pfmdr1 and pfcrt is part of the complex genetic background of CQR.

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Section: Discussionmentioning

confidence: 99%

Chloroquine susceptibility and reversibility in a Plasmodium falciparum genetic cross

Patel¹,

Drew²,

Tan³

et al. 2010

Molecular Microbiology

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“…Potential solutions to these problems, although not necessarily recognized at the time as being related to developing an attenuated sporozoite vaccine, were being reported. In 1975, a method for culturing P. falciparum in vitro was reported [26,27], followed by a method for producing gametocytes from these cultures in 1986 [28]. In 1986, it was reported that humans could be infected by the sporozoites produced in mosquitoes that had fed on these in vitro cultures [29].…”

Section: Developing Vaccine With Nuclear Technologymentioning

confidence: 99%

The Feasibility of Gamma Irradiation for Developing Malaria Vaccine

et al. 2011

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“…HB3, isolated from Central America (Honduras), represents a “wild-type” parasite sensitive to the quinoline line of drugs [35], while Dd2 was derived from a Laotian patient in whom chloroquine (CQ) therapy failed [36]. Dd2 is also resistant to pyrimethamine, as is typical of multidrug resistant (MDR) parasites.…”

Section: Introductionmentioning

confidence: 99%

Regulatory Hotspots in the Malaria Parasite Genome Dictate Transcriptional Variation

et al. 2008

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The determinants of transcriptional regulation in malaria parasites remain elusive. The presence of a well-characterized gene expression cascade shared by different Plasmodium falciparum strains could imply that transcriptional regulation and its natural variation do not contribute significantly to the evolution of parasite drug resistance. To clarify the role of transcriptional variation as a source of stain-specific diversity in the most deadly malaria species and to find genetic loci that dictate variations in gene expression, we examined genome-wide expression level polymorphisms (ELPs) in a genetic cross between phenotypically distinct parasite clones. Significant variation in gene expression is observed through direct co-hybridizations of RNA from different P. falciparum clones. Nearly 18% of genes were regulated by a significant expression quantitative trait locus. The genetic determinants of most of these ELPs resided in hotspots that are physically distant from their targets. The most prominent regulatory locus, influencing 269 transcripts, coincided with a Chromosome 5 amplification event carrying the drug resistance gene, pfmdr1, and 13 other genes. Drug selection pressure in the Dd2 parental clone lineage led not only to a copy number change in the pfmdr1 gene but also to an increased copy number of putative neighboring regulatory factors that, in turn, broadly influence the transcriptional network. Previously unrecognized transcriptional variation, controlled by polymorphic regulatory genes and possibly master regulators within large copy number variants, contributes to sweeping phenotypic evolution in drug-resistant malaria parasites.

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Plasmodium falciparum Gametocytes from Culture in Vitro Develop to Sporozoites That Are Infectious to Primates

Cited by 32 publications

References 20 publications

Chloroquine susceptibility and reversibility in a Plasmodium falciparum genetic cross

Chloroquine susceptibility and reversibility in a Plasmodium falciparum genetic cross

The Feasibility of Gamma Irradiation for Developing Malaria Vaccine

Regulatory Hotspots in the Malaria Parasite Genome Dictate Transcriptional Variation

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