scholarly journals The endosymbiotic origins of the apicoplast link fever-survival and artemisinin-resistance in the malaria parasite

2020 ◽  
Author(s):  
Min Zhang ◽  
Chengqi Wang ◽  
Jenna Oberstaller ◽  
Phaedra Thomas ◽  
Thomas D. Otto ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Heat Shock ◽  
Large Scale ◽  
Artemisinin Resistance ◽  
Free Living ◽  
Artemisinin Derivatives ◽  
Evolutionary Origins ◽  
Algal Endosymbiont ◽  
Phenotype Screen ◽  
Artemisinin Combination Therapies

ABSTRACTBackgroundThe emergence and spread of Plasmodium falciparum parasites resistant to front-line antimalarial artemisinin-combination therapies (ACT) threatens to erase the considerable gains against the disease of the last decade. We developed a new large-scale phenotypic screening pipeline and used it to carry out the first large-scale forward-genetic phenotype screen in P. falciparum to identify genes that allow parasites to survive febrile temperatures.ResultsScreening identified more than 200 P. falciparum mutants with differential responses to increased temperature. These mutants were more likely to be sensitive to artemisinin derivatives as well as to heightened oxidative stress. Major processes critical for P. falciparum tolerance to febrile temperatures and artemisinin included highly essential, conserved pathways associated with protein-folding, heat-shock and proteasome-mediated degradation, and unexpectedly, isoprenoid biosynthesis, which originated from the parasite’s algal endosymbiont-derived plastid, the apicoplast. Apicoplast-targeted genes in general were up-regulated in response to heat shock, as were other Plasmodium genes with orthologs in plant and algal genomes.ConclusionsPlasmodium falciparum parasites appear to exploit their innate febrile-response mechanisms to mediate resistance to artemisinin. Both responses depend on endosymbiotic cyanobacterium-related ancestral genes in the parasite’s genome, suggesting a link to the evolutionary origins of Plasmodium parasites in free-living ancestors.

scholarly journals The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Min Zhang ◽  
Chengqi Wang ◽  
Jenna Oberstaller ◽  
Phaedra Thomas ◽  
Thomas D. Otto ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Heat Shock ◽  
Large Scale ◽  
Artemisinin Resistance ◽  
Free Living ◽  
Artemisinin Derivatives ◽  
Evolutionary Origins ◽  
Algal Endosymbiont ◽  
Phenotype Screen ◽  
Artemisinin Combination Therapies

AbstractThe emergence and spread of Plasmodium falciparum parasites resistant to front-line antimalarial artemisinin-combination therapies (ACT) threatens to erase the considerable gains against the disease of the last decade. Here, we develop a large-scale phenotypic screening pipeline and use it to carry out a large-scale forward-genetic phenotype screen in P. falciparum to identify genes allowing parasites to survive febrile temperatures. Screening identifies more than 200 P. falciparum mutants with differential responses to increased temperature. These mutants are more likely to be sensitive to artemisinin derivatives as well as to heightened oxidative stress. Major processes critical for P. falciparum tolerance to febrile temperatures and artemisinin include highly essential, conserved pathways associated with protein-folding, heat shock and proteasome-mediated degradation, and unexpectedly, isoprenoid biosynthesis, which originated from the ancestral genome of the parasite’s algal endosymbiont-derived plastid, the apicoplast. Apicoplast-targeted genes in general are upregulated in response to heat shock, as are other Plasmodium genes with orthologs in plant and algal genomes. Plasmodium falciparum parasites appear to exploit their innate febrile-response mechanisms to mediate resistance to artemisinin. Both responses depend on endosymbiont-derived genes in the parasite’s genome, suggesting a link to the evolutionary origins of Plasmodium parasites in free-living ancestors.

scholarly journals Emergence and Spread of kelch13 Mutations Associated with Artemisinin Resistance in Plasmodium falciparum Parasites in 12 Thai Provinces from 2007 to 2016

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Theerayot Kobasa ◽  
Eldin Talundzic ◽  
Rungniran Sug-aram ◽  
Patcharida Boondat ◽  
Ira F. Goldman ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Gene Mutations ◽  
Artemisinin Resistance ◽  
Parasite Clearance ◽  
Resistance Mutations ◽  
Content Type ◽  
Artemisinin Derivatives ◽  
Reduced Ring ◽  
Control And Prevention ◽  
Greater Mekong Subregion

ABSTRACT Artemisinin-based combination therapy (ACT) is the most effective and widely used treatment for uncomplicated Plasmodium falciparum malaria and is a cornerstone for malaria control and prevention globally. Resistance to artemisinin derivatives has been confirmed in the Greater Mekong Subregion (GMS) and manifests as slow parasite clearance in patients and reduced ring stage susceptibility to artemisinins in survival assays. The P. falciparum kelch13 gene mutations associated with artemisinin-resistant parasites are now widespread in the GMS. We genotyped 277 samples collected during an observational study from 2012 to 2016 from eight provinces in Thailand to identify P. falciparum kelch13 mutations. The results were combined with previously reported genotyping results from Thailand to construct a map illustrating the evolution of P. falciparum kelch13 mutations from 2007 to 2016 in that country. Different mutant alleles were found in strains with different geographical origins. The artemisinin resistance-conferring Y493H and R539T mutations were detected mainly in eastern Thailand (bordering Cambodia), while P574L was found only in western Thailand and R561H only in northwestern Thailand. The C580Y mutation was found across the entire country and was nearing fixation along the Thai-Cambodia border. Overall, the prevalence of artemisinin resistance mutations increased over the last 10 years across Thailand, especially along the Thai-Cambodia border. Molecular surveillance and therapeutic efficacy monitoring should be intensified in the region to further assess the extent and spread of artemisinin resistance.

scholarly journals Polymorphisms in Plasmodium falciparum Kelch 13 and P. vivax Kelch 12 Genes in Parasites Collected from Three South Pacific Countries Prior to Extensive Exposure to Artemisinin Combination Therapies

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Karryn Gresty ◽  
Karen Anderson ◽  
Cielo Pasay ◽  
Norman C. Waters ◽  
Qin Cheng
Keyword(s):  
Plasmodium Falciparum ◽  
Papua New Guinea ◽  
Solomon Islands ◽  
Artemisinin Resistance ◽  
South Pacific ◽  
New Guinea ◽  
Combination Therapies ◽  
Baseline Information ◽  
Artemisinin Combination Therapies ◽  
Kelch 13

ABSTRACT The South Pacific countries Solomon Islands, Vanuatu, and Papua New Guinea (PNG) adopted artemisinin-based combination therapies (ACTs) in 2008. We examined Kelch 13 and Kelch 12 genes in parasites originating from these countries before or at ACT introduction. Four Kelch 13 and two Kelch 12 novel sequence polymorphisms, not associated with artemisinin resistance, were observed in parasites from Solomon Islands and Vanuatu. No polymorphisms were observed in PNG parasites. The findings provide useful baseline information.

scholarly journals The Malaria TaqMan Array Card Includes 87 Assays for Plasmodium falciparum Drug Resistance, Identification of Species, and Genotyping in a Single Reaction

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Suporn Pholwat ◽  
Jie Liu ◽  
Suzanne Stroup ◽  
Shevin T. Jacob ◽  
Patrick Banura ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Large Scale ◽  
Limit Of Detection ◽  
Artemisinin Resistance ◽  
Clinical Samples ◽  
Content Type ◽  
Antimalarial Resistance ◽  
Resistance Markers ◽  
Taqman Array

ABSTRACT Antimalarial drug resistance exacerbates the global disease burden and complicates eradication efforts. To facilitate the surveillance of resistance markers in countries of malaria endemicity, we developed a suite of TaqMan assays for known resistance markers and compartmentalized them into a single array card (TaqMan array card, TAC). We included 87 assays for species identification, for the detection of Plasmodium falciparum mutations associated with chloroquine, atovaquone, pyrimethamine, sulfadoxine, and artemisinin resistance, and for neutral single nucleotide polymorphism (SNP) genotyping. Assay performance was first optimized using DNA from common laboratory parasite lines and plasmid controls. The limit of detection was 0.1 to 10 pg of DNA and yielded 100% accuracy compared to sequencing. The tool was then evaluated on 87 clinical blood samples from around the world, and the malaria TAC once again achieved 100% accuracy compared to sequencing and in addition detected the presence of mixed infections in clinical samples. With its streamlined protocol and high accuracy, this malaria TAC should be a useful tool for large-scale antimalarial resistance surveillance.

scholarly journals Little Polymorphism at the K13 Propeller Locus in Worldwide Plasmodium falciparum Populations Prior to the Introduction of Artemisinin Combination Therapies

2016 ◽  
Vol 60 (6) ◽  
pp. 3340-3347 ◽  
Author(s):  
Toshihiro Mita ◽  
Richard Culleton ◽  
Nobuyuki Takahashi ◽  
Masatoshi Nakamura ◽  
Takahiro Tsukahara ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Haplotype Diversity ◽  
Artemisinin Resistance ◽  
Pairwise Comparison ◽  
Purifying Selection ◽  
Parasite Clearance ◽  
Combination Therapies ◽  
Content Type ◽  
Exposed Population ◽  
Artemisinin Combination Therapies

The emergence and spread of artemisinin-resistantPlasmodium falciparumis of huge concern for the global effort toward malaria control and elimination. Artemisinin resistance, defined as a delayed time to parasite clearance following administration of artemisinin, is associated with mutations in thePfkelch13gene of resistant parasites. To date, as many as 60 nonsynonymous mutations have been identified in this gene, but whether these mutations have been selected by artemisinin usage or merely reflect natural polymorphism independent of selection is currently unknown. To clarify this, we sequenced thePfkelch13propeller domain in 581 isolates collected before (420 isolates) and after (161 isolates) the implementation of artemisinin combination therapies (ACTs), from various regions of endemicity worldwide. Nonsynonymous mutations were observed in 1% of parasites isolated prior to the introduction of ACTs. Frequencies of mutant isolates, nucleotide diversity, and haplotype diversity were significantly higher in the parasites isolated from populations exposed to artemisinin than in those from populations that had not been exposed to the drug. In the artemisinin-exposed population, a significant excess of dN compared to dS was observed, suggesting the presence of positive selection. In contrast, pairwise comparison of dN and dS and the McDonald and Kreitman test indicate that purifying selection acts on thePfkelch13propeller domain in populations not exposed to ACTs. These population genetic analyses reveal a low baseline ofPfkelch13polymorphism, probably due to purifying selection in the absence of artemisinin selection. In contrast, variousPfkelch13mutations have been selected under artemisinin pressure.

scholarly journals Artemether and Praziquantel: Origin, Mode of Action, Impact, and Suggested Application for Effective Control of Human Schistosomiasis

2018 ◽  
Vol 3 (4) ◽  
pp. 125 ◽  
Author(s):  
Robert Bergquist ◽  
Hala Elmorshedy
Keyword(s):  
Egg Production ◽  
Large Scale ◽  
Artemisinin Resistance ◽  
Effective Control ◽  
Artemisinin Derivatives ◽  
Malaria Therapy ◽  
Molecular Approaches ◽  
Life Cycle Stages ◽  
Praziquantel Treatment ◽  
Large Scale Field

The stumbling block for the continued, single-drug use of praziquantel (PZQ) against schistosomiasis is less justified by the risk of drug resistance than by the fact that this drug is inactive against juvenal parasites, which will mature and start egg production after chemotherapy. Artemisinin derivatives, currently used against malaria in the form of artemisinin-based combination therapy (ACT), provide an opportunity as these drugs are not only active against malaria plasmodia, but surprisingly also against juvenile schistosomes. An artemisinin/PZQ combination would be complimentary, and potentially additive, as it would kill two schistosome life cycle stages and thus confer a transmission-blocking modality to current chemotherapy. We focus here on single versus combined regimens in endemic settings. Although the risk of artemisinin resistance, already emerging with respect to malaria therapy in Southeast Asia, prevents use in countries where ACT is needed for malaria care, an artemisinin-enforced praziquantel treatment (APT) should be acceptable in North Africa (including Egypt), the Middle East, China, and Brazil, as these countries are not endemic for malaria. Thanks to recent progress with respect to high-resolution diagnostics, based on circulating schistosome antigens in humans and molecular approaches for snail surveys, it should be possible to keep areas scheduled for schistosomiasis elimination under surveillance, bringing rapid response to bear on problems arising. The next steps would be to investigate where and for how long APT should be applied to make a lasting impact. A large-scale field trial in an area with modest transmission should tell how apt this approach is.

scholarly journals Molecular assessment of kelch13 non-synonymous mutations in Plasmodium falciparum isolates from Central African Republic (2017–2019)

2020 ◽  
Author(s):  
Romaric Nzoumbou-Boko ◽  
Chris-Boris Gildas Panté-Wockama ◽  
Carine Ngoagoni ◽  
Nathalie Petiot ◽  
Eric Legrand ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Southeast Asia ◽  
Central African Republic ◽  
Artemisinin Resistance ◽  
Plasmodium Species ◽  
Sub Saharan Africa ◽  
Artemisinin Derivatives ◽  
Synonymous Mutations

Abstract Background: Over the last decade, Artemisinin-based Combination Therapies (ACT) have contributed substantially to the decrease in malaria-related morbidity and mortality. The emergence of Plasmodium falciparum parasites resistant to artemisinin derivatives in Southeast Asia and the risk of their spread or of local emergence in sub-Saharan Africa are a major threat to public health. This study thus set out to estimate the proportion of P. falciparum isolates, with PfKelch13 gene mutations associated with artemisinin resistance previously detected in Southeast Asia. Methods: Blood samples were collected in two sites of Bangui, the capital of the Central African Republic form 2017 to 2019. DNA was extracted and nested PCR were carried out to detect Plasmodium species and mutations in the propeller domain of the PfKelch13 gene. Results: A total of 255 P. falciparum isolates were analyzed. Among them, P. ovale DNA was found in four samples (1.57%, 4/255). Of 187 samples with interpretable PfKelch13 sequences, four isolates presented a mutation in the PfKelch13 gene (2.1%, 4/187), including one non-synonymous mutation (Y653N) (0.5%, 1/187). This mutation has never been described as associated with artemisinin resistance in Southeast Asia and its in vitro phenotype is unknown. Conclusion: This preliminary study indicates the need for a larger study on samples collected across the whole country along with the evaluation of in vitro and in vivo phenotype profiles of PfKelch13 mutant parasites to estimate the risk of artemisinin resistance in the CAR.

scholarly journals Artemisinin-Based Antimalarial Drug Therapy: Molecular Pharmacology and Evolving Resistance

2019 ◽  
Vol 4 (2) ◽  
pp. 89 ◽  
Author(s):  
Laura E. Heller ◽  
Paul D. Roepe
Keyword(s):  
Plasmodium Falciparum ◽  
Artemisinin Resistance ◽  
Standard Of Care ◽  
Plasmodium Falciparum Malaria ◽  
Genetic Mutations ◽  
South East Asia ◽  
Molecular Pharmacology ◽  
Combination Therapies ◽  
The World ◽  
Artemisinin Combination Therapies

The molecular pharmacology of artemisinin (ART)-based antimalarial drugs is incompletely understood. Clinically, these drugs are used in combination with longer lasting partner drugs in several different artemisinin combination therapies (ACTs). ACTs are currently the standard of care against Plasmodium falciparum malaria across much of the world. A harbinger of emerging artemisinin resistance (ARTR), known as the delayed clearance phenotype (DCP), has been well documented in South East Asia (SEA) and is beginning to affect the efficacy of some ACTs. Though several genetic mutations have been associated with ARTR/DCP, a molecular mechanism remains elusive. This paper summarizes our current understanding of ART molecular pharmacology and hypotheses for ARTR/DCP.

scholarly journals Artemisinin-Resistant Plasmodium falciparum Parasites Exhibit Altered Patterns of Development in Infected Erythrocytes

2015 ◽  
Vol 59 (6) ◽  
pp. 3156-3167 ◽  
Author(s):  
Amanda Hott ◽  
Debora Casandra ◽  
Kansas N. Sparks ◽  
Lindsay C. Morton ◽  
Geocel-Grace Castanares ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Artemisinin Resistance ◽  
Drug Pressure ◽  
Content Type ◽  
Phenotypic Resistance ◽  
Artemisinin Derivatives ◽  
Stage Of Development ◽  
Clinical Resistance

ABSTRACTArtemisinin derivatives are used in combination with other antimalarial drugs for treatment of multidrug-resistant malaria worldwide. Clinical resistance to artemisinin recently emerged in southeast Asia, yetin vitrophenotypes for discerning mechanism(s) of resistance remain elusive. Here, we describe novel phenotypic resistance traits expressed by artemisinin-resistantPlasmodium falciparum. The resistant parasites exhibit altered patterns of development that result in reduced exposure to drug at the most susceptible stage of development in erythrocytes (trophozoites) and increased exposure in the most resistant stage (rings). In addition, a novelin vitrodelayed clearance assay (DCA) that assesses drug effects on asexual stages was found to correlate with parasite clearance half-lifein vivoas well as with mutations in the Kelch domain gene associated with resistance (Pf3D7_1343700). Importantly, all of the resistance phenotypes were stable in cloned parasites for more than 2 years without drug pressure. The results demonstrate artemisinin-resistantP. falciparumhas evolved a novel mechanism of phenotypic resistance to artemisinin drugs linked to abnormal cell cycle regulation. These results offer insights into a novel mechanism of drug resistance inP. falciparumand new tools for monitoring the spread of artemisinin resistance.

scholarly journals Molecular assessment of kelch13 non-synonymous mutations in Plasmodium falciparum isolates from Central African Republic (2017–2019)

2020 ◽  
Author(s):  
Romaric Nzoumbou-Boko ◽  
Chris-Boris Gildas Panté-Wockama ◽  
Carine Ngoagoni ◽  
Nathalie Petiot ◽  
Eric Legrand ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Southeast Asia ◽  
Central African Republic ◽  
Artemisinin Resistance ◽  
Plasmodium Species ◽  
Sub Saharan Africa ◽  
Artemisinin Derivatives ◽  
Synonymous Mutations

Abstract Background: Over the last decade, Artemisinin-based Combination Therapies (ACT) have contributed substantially to the decrease in malaria-related morbidity and mortality. The emergence of Plasmodium falciparum parasites resistant to artemisinin derivatives in Southeast Asia and the risk of their spread or of local emergence in sub-Saharan Africa are a major threat to public health. This study thus set out to estimate the proportion of P. falciparum isolates, with PfKelch13 gene mutations associated with artemisinin resistance previously detected in Southeast Asia. Methods: Blood samples were collected in two sites of Bangui, the capital of the Central African Republic form 2017 to 2019. DNA was extracted and nested PCR were carried out to detect Plasmodium species and mutations in the propeller domain of the PfKelch13 gene. Results: A total of 255 P. falciparum isolates were analyzed. Among them, P. ovale DNA was found in four samples (1.57%, 4/255). Of 187 samples with interpretable PfKelch13 sequences, four isolates presented a mutation in the PfKelch13 gene (2.1%, 4/187), including one non-synonymous mutation (Y653N) (0.5%, 1/187). This mutation has never been described as associated with artemisinin resistance in Southeast Asia and its in vitro phenotype is unknown. Conclusion: This preliminary study indicates the need for a larger study on samples collected across the whole country along with the evaluation of in vitro and in vivo phenotype profiles of PfKelch13 mutant parasites to estimate the risk of artemisinin resistance in the CAR.

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