Journal ArticleDOI
Routine In Vitro Culture of Plasmodium falciparum: Experimental Consequences?
Sandra Duffy,Vicky M. Avery +1 more
TLDR
It is reasoned that culture conditions should be re-established as a primary consideration in in vitro malaria experimentation.About:
This article is published in Trends in Parasitology.The article was published on 2018-07-01. It has received 23 citations till now.read more
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Journal ArticleDOI
Inhibition of Resistance-Refractory P. falciparum Kinase PKG Delivers Prophylactic, Blood Stage, and Transmission-Blocking Antiplasmodial Activity
Manu Vanaerschot,James M. Murithi,Charisse Flerida A. Pasaje,Sonja Ghidelli-Disse,Louis Dwomoh,Megan J. Bird,Natasha Spottiswoode,Nimisha Mittal,Lauren B. Arendse,Edward Owen,Kathryn J. Wicht,Giulia Siciliano,Markus Bösche,Tomas Yeo,T. R. Santha Kumar,Sachel Mok,Emma F. Carpenter,Marla J. Giddins,Olalla Sanz,Sabine Ottilie,Pietro Alano,Kelly Chibale,Manuel Llinás,Anne-Catrin Uhlemann,Michael J. Delves,Andrew B. Tobin,Christian Doerig,Christian Doerig,Elizabeth A. Winzeler,Marcus C. S. Lee,Jacquin C. Niles,David A. Fidock +31 more
TL;DR: It is shown that the trisubstituted imidazole MMV030084 potently inhibits hepatocyte invasion by Plasmodium sporozoites, merozoite egress from asexual blood stage schizonts, and male gamete exflagellation.
A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria
Alassane Mbengue,Souvik Bhattacharjee,Trupti Pandharkar,Liu Liu,Guillermina Estiu,Robert V. Stahelin,Shahir S. Rizk,Dieudonné Lemuh Njimoh,Yana Ryan,Kesinee Chotivanich,Chea Nguon,Mehdi Ghorbal,Jose-Juan Lopez-Rubio,Michael E. Pfrender,Scott J. Emrich,Narla Mohandas,Arjen M. Dondorp,Olaf Wiest,Kasturi Haldar +18 more
Abstract: Artemisinins are the cornerstone of anti-malarial drugs. Emergence and spread of resistance to them raises risk of wiping out recent gains achieved in reducing worldwide malaria burden and threatens future malaria control and elimination on a global level. Genome-wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase, as well as its lipid product phosphatidylinositol-3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signalling in which transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination.
Journal ArticleDOI
Artemisinin exposure at the ring or trophozoite stage impacts Plasmodium falciparum sexual conversion differently
Harvie P. Portugaliza,Harvie P. Portugaliza,Harvie P. Portugaliza,Shinya Miyazaki,Fiona J. A. Geurten,Christopher Pell,Anna Rosanas-Urgell,Chris J. Janse,Alfred Cortés +8 more
TL;DR: Exposure to subcurative doses of the frontline antimalarial drug dihydroartemisinin at the trophozoite stage resulted in a ~ fourfold increase in sexual conversion, and no increase was observed when ring stages were exposed or in cultures in which sexual conversion was stimulated by choline depletion.
Journal ArticleDOI
Transcriptional variation in malaria parasites: why and how
TL;DR: How epigenetic variation, directed transcriptional responses and also genetic changes that affect transcript levels can all contribute to transcriptional variation and, ultimately, parasite survival are discussed.
Journal ArticleDOI
Schizont transcriptome variation among clinical isolates and laboratory-adapted clones of the malaria parasite Plasmodium falciparum
Sarah J. Tarr,Ofelia Díaz-Ingelmo,Lindsay B. Stewart,Suzanne E. Hocking,Lee G. Murray,Craig W. Duffy,Thomas D. Otto,Thomas D. Otto,Lia Chappell,Julian C. Rayner,Gordon A. Awandare,David J. Conway +11 more
TL;DR: Analysis of multiple biological sample replicates greatly improves identification of genes variably expressed between different cultured parasite lines.
References
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Journal ArticleDOI
Improved In Vitro Culture of Plasmodium falciparum Permits Establishment of Clinical Isolates with Preserved Multiplication, Invasion and Rosetting Phenotypes
Ulf Ribacke,Kirsten Moll,Letusa Albrecht,Hodan Ahmed Ismail,Johan Normark,Emilie Flaberg,Laszlo Szekely,Kjell Hultenby,Kristina E. M. Persson,Thomas G. Egwang,Mats Wahlgren +10 more
TL;DR: It is suggested that rosetting enhances the ability of the parasite to multiply within the human host.
Journal ArticleDOI
Serum Lipoproteins Promote Efficient Presentation of the Malaria Virulence Protein PfEMP1 at the Erythrocyte Surface
Sarah Frankland,Salenna R. Elliott,Francisca Yosaatmadja,James G. Beeson,Stephen J. Rogerson,Akinola Adisa,Leann Tilley +6 more
TL;DR: It is shown that efficient presentation of the A4 and VAR2CSA variants of Pf EMP1 is dependent on the presence of serum in the bathing medium during parasite maturation, and analysis of the serum components reveals that lipoproteins, especially those of the low-density lipoprotein fraction, promote PfEMP1 presentation.
Journal ArticleDOI
The role of the red blood cell in host defence against falciparum malaria: an expanding repertoire of evolutionary alterations
TL;DR: A better understanding of how changes in RBC physiology impact malaria pathogenesis may uncover new strategies to combat the disease.
Journal ArticleDOI
Phenotypic Screens in Antimalarial Drug Discovery.
TL;DR: This review highlights recent advances and progress toward phenotypic screening methodologies over the past several years, with a focus on exoerythrocytic stage screens.
Journal ArticleDOI
Bioenergetics-based modeling of Plasmodium falciparum metabolism reveals its essential genes, nutritional requirements, and thermodynamic bottlenecks.
Anush Chiappino-Pepe,Stepan Tymoshenko,Meriç Ataman,Dominique Soldati-Favre,Vassily Hatzimanikatis +4 more
TL;DR: A genome-scale metabolic model (iPfa) of the deadliest malaria parasite, Plasmodium falciparum, and its thermodynamics-based flux analysis (TFA) is presented, providing novel insight into the metabolic needs and capabilities of the malaria parasite.
Related Papers (5)
Plasmodium falciparum in vitro continuous culture conditions: A comparison of parasite susceptibility and tolerance to anti-malarial drugs throughout the asexual intra-erythrocytic life cycle.
Sandra Duffy,Vicky M. Avery +1 more