Eliminating Malaria

Fidock, David A.

doi:10.1126/science.1240539

Cited by 20 publications

(19 citation statements)

References 16 publications

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“…Laboratories with primate malaria research facilities, such as exist in the USA and the Netherlands, might be able to follow up on this aspect of the in vivo research that was conducted during the 1980s. Studies on the biological nature and biochemical structure of hypnozoites are needed to inform drug discovery and vaccinology and thereby contribute to the ultimate goal of eliminating malaria [83]. What causes dormant malaria parasites to become activated (hypnozoites) or reactivated (putative latent extrahepatic and nonbloodstream merozoites)?…”

Section: Box 3 Outstanding Questions and Research Directions (Also Smentioning

confidence: 99%

Do hypnozoites cause relapse in malaria?

Markus

2015

Trends in Parasitology

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Section: Box 3 Outstanding Questions and Research Directions (Also Smentioning

confidence: 99%

Do hypnozoites cause relapse in malaria?

Markus

2015

Trends in Parasitology

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“…Achieving this ultimate goal is challenging, as malaria claims nearly 440,000 lives annually, and nearly half of the world's population is at risk of contracting the disease (3). The emergence of parasites resistant to current therapeutics (5-7) and mosquito vectors impervious to insecticides (8) causes considerable concern for the sustained progress of the strategy (9).…”

mentioning

confidence: 99%

Luciferase-Based, High-Throughput Assay for Screening and Profiling Transmission-Blocking Compounds against Plasmodium falciparum Gametocytes

Lucantoni

Fidock

Avery

2016

Antimicrob Agents Chemother

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The discovery of new antimalarial drugs able to target both the asexual and gametocyte stages of Plasmodium falciparum is critical to the success of the malaria eradication campaign. We have developed and validated a robust, rapid, and cost-effective highthroughput reporter gene assay to identify compounds active against late-stage (stage IV and V) gametocytes. The assay, which is suitable for testing compound activity at incubation times up to 72 h, demonstrates excellent quality and reproducibility, with average Z= values of 0.85 ؎ 0.01. We used the assay to screen more than 10,000 compounds from three chemically diverse libraries. The screening outcomes highlighted the opportunity to use collections of compounds with known activity against the asexual stages of the parasites as a starting point for gametocytocidal activity detection in order to maximize the chances of identifying gametocytocidal compounds. This assay extends the capabilities of our previously reported luciferase assay, which tested compounds against early-stage gametocytes, and opens possibilities to profile the activities of gametocytocidal compounds over the entire course of gametocytogenesis.T he complex life cycle of the Plasmodium falciparum parasite, responsible for malaria, involves a human host, in which the intraerythrocytic asexual stages of the parasite cause the disease manifestations, and an anopheline mosquito vector, in which the parasite transmission stages genetically recombine and develop to successfully infect new human hosts. Parasite transmission to both the mosquito vector and the next human host rely on the sexual stage gametocytes. In P. falciparum, gametocytes emerge in low numbers from the asexual population and mature over a 10-to 12-day period, progressing through five morphologically distinct stages (I to V) (1). Mature stage V gametocytes can remain infective to the mosquito for an extended time, even if the asexual parasite population has been decreased by therapeutic drugs (2).The last 15 years have witnessed an unprecedented effort in the fight against malaria, with the deployment of large-scale interventions, including the distribution of artemisinin-based combination therapies (ACTs); targeted chemoprophylaxis of patient populations at particular risk, notably pregnant women and children under the age of 5 years; and vector control measures, including insecticide-treated bed nets. As a result, a 48% decrease in global malaria mortality rates was achieved between 2000 and 2015, and 16 countries have successfully eliminated malaria since 2010 (3). Although these impressive achievements have required a substantial economic outlay, it has become increasingly clear that an aggressive strategy aimed at malaria eradication is the only sustainable, albeit ambitious, goal in the long term (4). Achieving this ultimate goal is challenging, as malaria claims nearly 440,000 lives annually, and nearly half of the world's population is at risk of contracting the disease (3). The emergence of parasites resistant to current ...

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“…In particular, RAD5 is a DNA clamp that is involved in the DNA damage tolerance pathway that promotes the repair of discontinuities [11][12][13]. In yeast, mutations in this gene have been implicated in cell cycle arrest [13,14], and thus, a similar role may be expected in P. falciparum [15], which might lead to delayed clearance following artemisinin treatment.…”

Section: Introductionmentioning

confidence: 95%

Global distribution of polymorphisms associated with delayed Plasmodium falciparum parasite clearance following artemisinin treatment: Genotyping of archive blood samples

Murai

Culleton

Hisaoka

et al. 2015

Parasitology International

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The recent emergence and spread of artemisinin-resistant Plasmodium falciparum isolates is a growing concern for global malaria-control efforts. A recent genome-wide analysis study identified two SNPs at genomic positions MAL10-688956 and MAL13-1718319, which are linked to delayed clearance of parasites following artemisinin combination therapy (ACT). It is expected that continuous artemisinin pressure will affect the distribution of these SNPs. Here, we investigate the worldwide distribution of these SNPs using a large number of archived samples in order to generate baseline data from the period before the emergence of ACT resistance. The presence of SNPs in MAL10-688956 and MAL13-1718319 was assessed by nested PCR RFLP and direct DNA sequencing using 653 global P. falciparum samples obtained before the reported emergence of ACT resistance. SNPs at MAL10-688956 and MAL13-1718319 associated with delayed parasite clearance following ACT administration were observed in 8% and 3% of parasites, respectively, mostly in Cambodia and Thailand. Parasites harbouring both SNPs were found in only eight (1%) isolates, all of which were from Cambodia and Thailand. Linkage disequilibrium was detected between MAL10-688956 and MAL13-1718319, suggesting that this SNP combination may have been selected by ACT drug pressure. Neither of the SNPs associated with delayed parasite clearance were observed in samples from Africa or South America. Baseline information of the geographical difference of MAL10-688956 and MAL13-1718319 SNPs provides a solid basis for assessing whether these SNPs are selected by artemisinin-based combination therapies.

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Eliminating Malaria

Abstract: Global eradication requires concerted efforts to combat emerging resistance to the potent antimalarial artemisinin.

Cited by 20 publications

References 16 publications

Do hypnozoites cause relapse in malaria?

Do hypnozoites cause relapse in malaria?

Luciferase-Based, High-Throughput Assay for Screening and Profiling Transmission-Blocking Compounds against Plasmodium falciparum Gametocytes

Global distribution of polymorphisms associated with delayed Plasmodium falciparum parasite clearance following artemisinin treatment: Genotyping of archive blood samples

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