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| Open AccessPareto rules for malaria super-spreaders and super-spreading
Investigating malaria transmission at three sites in Uganda, the authors identify super-spreaders and show that super-spreading is more prominent at low-intensity transmission, and that seasonality and environmental stochasticity have a greater influence on super-spreading.
- Laura Cooper
- , Su Yun Kang
- & David L. Smith
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| Open AccessGenetic manipulation of cell line derived reticulocytes enables dissection of host malaria invasion requirements
Here, the authors show that reticulocytes derived from immortalized erythroblasts support invasion and development of Plasmodium falciparum and use CRISPR-mediated gene knockout and complementation of an invasion receptor to demonstrate utility of this model system for research in malaria invasion.
- Timothy J. Satchwell
- , Katherine E. Wright
- & Jake Baum
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| Open AccessRobust continuous in vitro culture of the Plasmodium cynomolgi erythrocytic stages
Present understanding of Plasmodium vivax biology is hampered by its inability to grow in vitro. Here, the authors developed an in vitro culture of its simian counterpart, P. cynomolgi, which shares morphological and phenotypic similarities with P. vivax, initiating a new phase in vivax research.
- Adeline C. Y. Chua
- , Jessica Jie Ying Ong
- & Pablo Bifani
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Article
| Open AccessPlasmodium myosin A drives parasite invasion by an atypical force generating mechanism
Here, Robert-Paganin et al. show that myosin A from Plasmodium falciparum is critical for red blood cell invasion and that non-canonical interactions and regulated phosphorylation are important for force generation during parasite invasion.
- Julien Robert-Paganin
- , James P. Robblee
- & Anne Houdusse
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Article
| Open AccessAntimalarial activity of primaquine operates via a two-step biochemical relay
Primaquine (PQ) is a widely used anti-malaria drug, but its mechanism of action is unclear. Here, Camarda et al. show that PQ’s activity against liver and sexual Plasmodium stages depends on generation of hydroxylated-PQ metabolites (OH-PQm), which, undergoing further reactions, results in production of H2O2.
- Grazia Camarda
- , Piyaporn Jirawatcharadech
- & Giancarlo A. Biagini
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| Open AccessGenomic structure and diversity of Plasmodium falciparum in Southeast Asia reveal recent parasite migration patterns
Understanding genomic variation in Plasmodium falciparum parasites and inferring migration patterns can guide malaria elimination strategies. Using genome-wide data for 1722 parasites collected from 54 districts, the authors use identity-by-descent approaches to estimate regional parasite migration and spread of artemisinin drug resistance.
- Amol C. Shetty
- , Christopher G. Jacob
- & Marie A. Onyamboko
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Article
| Open AccessThe economics of malaria control in an age of declining aid
Foreign aid is necessary to control tropical diseases in endemic countries. Here the authors outline the steps taken to control malaria in Africa since 2000 and present an economic model to propose that US$25−30 per capita will be needed to avoid a disease trap.
- Eric Maskin
- , Célestin Monga
- & Jean-Claude Berthélemy
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Article
| Open AccessHuman mobility patterns and malaria importation on Bioko Island
Malaria on Bioko Island has been reduced substantially but many acquire malaria while traveling. Here, the authors use survey data, geostatistical and mathematical modeling to investigate malaria prevalence and mobility patterns and find that in some parts of the island a significant fraction of prevalence is attributable to malaria acquired while traveling.
- Carlos A. Guerra
- , Su Yun Kang
- & David L. Smith
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Article
| Open AccessPlasmodium falciparum sexual differentiation in malaria patients is associated with host factors and GDV1-dependent genes
Here, the authors quantify early gametocyte-committed ring (gc-ring) stage Plasmodium falciparum parasites in 260 malaria patients 10 days before maturation to transmissible stage V gametocytes, and show that the ratio of circulating gc-rings is positively correlated with parasitemia and negatively correlated with body temperature.
- Miho Usui
- , Surendra K. Prajapati
- & Kim C. Williamson
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Article
| Open AccessA defined mechanistic correlate of protection against Plasmodium falciparum malaria in non-human primates
Proof of protection against blood-stage P. falciparum malaria by a single immunological mechanism has been elusive. Here, using engineered anti-PfRH5 chimeric monoclonal antibodies in non-human primates, the authors show that high levels of merozoite-neutralizing antibodies can achieve protection.
- Alexander D. Douglas
- , G. Christian Baldeviano
- & Simon J. Draper
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| Open AccessThe temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density
The role of subpatent infections for malaria transmission and elimination is unclear. Here, Slater et al. analyse several malaria datasets to quantify the density, detectability, course of infection and infectiousness of subpatent infections.
- Hannah C. Slater
- , Amanda Ross
- & Lucy C Okell
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Article
| Open AccessThe indirect health effects of malaria estimated from health advantages of the sickle cell trait
Estimates of the burden of malaria often don't take wider, indirect effects on overall health into consideration. Here, Uyoga et al. estimate the indirect impact of malaria on children’s health in a case-control study, using the sickle cell trait as a proxy indicator for an effective intervention.
- Sophie Uyoga
- , Alex W. Macharia
- & Thomas N. Williams
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| Open AccessTargets of complement-fixing antibodies in protective immunity against malaria in children
Antibodies against Plasmodium falciparum merozoites that fix complement can inhibit blood-stage replication. Here, Reiling et al. show that complement-fixing antibodies strongly correlate with protective immunity in children, identify the merozoite targets, and predict antigen combinations that should result in strong protection.
- Linda Reiling
- , Michelle J. Boyle
- & James G. Beeson
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Article
| Open AccessDual RNA-seq identifies human mucosal immunity protein Mucin-13 as a hallmark of Plasmodium exoerythrocytic infection
Host-parasite interactions during the exoerythrocytic stage of Plasmodium infection remains poorly understood. Using dual RNA-Seq, the authors show that human mucosal immunity protein mucin-13 is upregulated during Plasmodium hepatic-stage infection and marks infected cells independent of tested Plasmodium species.
- Gregory M. LaMonte
- , Pamela Orjuela-Sanchez
- & Elizabeth A. Winzeler
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Article
| Open AccessOptimal dosing of dihydroartemisinin-piperaquine for seasonal malaria chemoprevention in young children
Seasonal malaria chemoprevention provides substantial benefit for young children, but resistance to used drugs will likely develop. Here, Chotsiri et al. evaluate the use of dihydroartemisinin-piperaquine as a regimen in 179 children, and population-based simulations suggest that small children would benefit from a higher and extended dosage.
- Palang Chotsiri
- , Issaka Zongo
- & Joel Tarning
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Article
| Open AccessTranscriptomic meta-signatures identified in Anopheles gambiae populations reveal previously undetected insecticide resistance mechanisms
Increasing insecticide resistance of mosquitoes represents a public health threat, and underlying mechanisms are poorly understood. Here, Ingham et al. identify putative insecticide resistance genes in Anopheles gambiae populations across Africa and develop a web-based application that maps their expression.
- V. A. Ingham
- , S. Wagstaff
- & H. Ranson
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| Open AccessThe origins of malaria artemisinin resistance defined by a genetic and transcriptomic background
Mechanisms underlying increasing artemisinin resistance of Plasmodium in Southeast Asia remain unclear. Here, Zhu et al. integrate TWAS, GWAS and eQTL analyses for 773 P. falciparum isolates and identify genetic and transcriptomic backgrounds to artemisinin resistance.
- Lei Zhu
- , Jaishree Tripathi
- & Ye Htut
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Article
| Open AccessSystematic review of indoor residual spray efficacy and effectiveness against Plasmodium falciparum in Africa
Indoor residual spraying is a commonly used method for mosquito, and malaria, control and there are a number of available insecticides that are available for this. Here, the authors evaluate the efficacy of widely-used and novel insecticides against pyrethroid-resistant mosquitoes.
- Ellie Sherrard-Smith
- , Jamie T. Griffin
- & Thomas S. Churcher
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Article
| Open AccessInflammasome activation negatively regulates MyD88-IRF7 type I IFN signaling and anti-malaria immunity
The inflammasome is an essential component of inflammatory processes and the host response to infection. Here the authors show that inflammasome activation modulates MyD88-IRF7 type I IFN signalling and anti-malaria immunity.
- Xiao Yu
- , Yang Du
- & Rong-Fu Wang
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Article
| Open AccessAdrenal hormones mediate disease tolerance in malaria
Disease tolerance mechanisms counter the negative effects of infection without decreasing the pathogen load. Here, the authors show that in mouse models of malaria, such disease tolerance can be conferred by adrenal hormones, by preventing excessive inflammation and hypoglycemia.
- Leen Vandermosten
- , Thao-Thy Pham
- & Philippe E. Van den Steen
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Article
| Open AccessStructural delineation of potent transmission-blocking epitope I on malaria antigen Pfs48/45
Malaria protein Pfs48/45 is a promising transmission-blocking antigen targeted by antibodies. Here, the authors determine the structure of its transmission-blocking epitope I, and generate a humanized monoclonal antibody that binds Pfs48/45 with high affinity.
- Prasun Kundu
- , Anthony Semesi
- & Jean-Philippe Julien
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| Open AccessEpistasis studies reveal redundancy among calcium-dependent protein kinases in motility and invasion of malaria parasites
Despite functional optimisation during evolution of parasitism, most members of a calcium dependent protein kinase (CDPK) family show genetic redundancy in Plasmodium. Here, the authors screen 294 genetic interactions among protein kinases in Plasmodium and show how some CDPKs functionally interact to control motility and host cell invasion.
- Hanwei Fang
- , Ana Rita Gomes
- & Mathieu Brochet
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Article
| Open AccessPlasmodium co-infection protects against chikungunya virus-induced pathologies
Chikungunya virus (CHIKV) and Plasmodium co-infections have been reported in humans, but effects of the two pathogens on each other are unclear. Here, Teo et al. show in mice that Plasmodium infection affects CHIKV-specific T and B cell responses, leading to reduced joint inflammation.
- Teck-Hui Teo
- , Fok-Moon Lum
- & Lisa F. P. Ng
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| Open AccessStructural basis for recognition of the malaria vaccine candidate Pfs48/45 by a transmission blocking antibody
Pfs48/45 is a promising component for a transmission-blocking malaria vaccine. Here, the authors develop a system to produce full-length Pfs48/45 for immunisation, characterise a panel of monoclonal antibodies and determine the structure of a potent transmission-blocking epitope.
- Frank Lennartz
- , Florian Brod
- & Matthew K. Higgins
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| Open AccessNon-competitive resource exploitation within mosquito shapes within-host malaria infectivity and virulence
The evolution of within-host malaria virulence has been studied, but the vector’s contribution isn’t well understood. Here, Costa et al. show that non-competitive parasitic resource exploitation within-vector, in particular lipid trafficking, restricts within-host infectivity and virulence of the parasite.
- G. Costa
- , M. Gildenhard
- & E. A. Levashina
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| Open AccessMathematical modelling of the impact of expanding levels of malaria control interventions on Plasmodium vivax
Plasmodium vivax poses a unique challenge for malaria elimination worldwide. Here, White et al. develop an individual-based mathematical model of P. vivax transmission and evaluate intervention strategies in Papua New Guinea.
- Michael T. White
- , Patrick Walker
- & Ivo Mueller
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| Open AccessA mosquito salivary gland protein partially inhibits Plasmodium sporozoite cell traversal and transmission
Mosquito saliva can affect transmission of Plasmodium to mammalian hosts, but active saliva components or mechanisms are poorly understood. Here, the authors identify a mosquito saliva protein that binds Plasmodium sporozoites and inhibits cell traversal in vitro and sporozoite speed in mice.
- Tyler R. Schleicher
- , Jing Yang
- & Erol Fikrig
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Article
| Open AccessNeutralization of the Plasmodium-encoded MIF ortholog confers protective immunity against malaria infection
Plasmodium species produce an ortholog of the cytokine macrophage migration inhibitory factor, PMIF, which modulates the host inflammatory response to malaria. Here, the authors show that inhibition of PMIF may have translational benefits for managing malaria infections.
- Alvaro Baeza Garcia
- , Edwin Siu
- & Richard Bucala
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| Open AccessGenome-wide real-time in vivo transcriptional dynamics during Plasmodium falciparum blood-stage development
Transcriptomic analysis often doesn’t differentiate between newly synthesized and stabilized mRNAs. Using rapid 4-thiouracil incorporation, Painter et al. here define genome-wide active transcription throughout Plasmodium blood-stage developmental stages and identify associated regulatory DNA sequence motifs.
- Heather J. Painter
- , Neo Christopher Chung
- & Manuel Llinás
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| Open AccessEstimating spatiotemporally varying malaria reproduction numbers in a near elimination setting
Twenty one countries have been identified for malaria elimination by 2020 and their progress needs to be constantly evaluated. Here, the authors present a method that estimates individual reproduction numbers and their variation through time and space and use it to monitor elimination success in El Salvador between 2010 and 2016.
- Isobel Routledge
- , José Eduardo Romero Chevéz
- & Samir Bhatt
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| Open AccessChanges in genome organization of parasite-specific gene families during the Plasmodium transmission stages
The development of malaria parasites is controlled by coordinated changes in gene expression. Here, the authors show that the three-dimensional genome structure of human malaria parasites is strongly connected with transcriptional activity of specific gene families throughout the life cycles of Plasmodium falciparum and Plasmodium vivax parasites.
- Evelien M. Bunnik
- , Kate B. Cook
- & Karine G. Le Roch
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| Open AccessA comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum
Currently available platforms to study liver stage of Plasmodium species have limitations. Here, the authors show that primary human hepatocyte cultures in 384-well format support hypnozoite and other liver stage development and are suitable for drug and antibody screens.
- Alison Roth
- , Steven P. Maher
- & John H. Adams
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| Open AccessNetworks of genetic similarity reveal non-neutral processes shape strain structure in Plasmodium falciparum
Plasmodium has evolved high genetic diversity in var genes, which encode for the major blood-stage antigen. Here, He et al. show how immune selection shapes the var gene repertoire in both simulated systems and a population in Ghana, by using neutral models and genetic similarity networks.
- Qixin He
- , Shai Pilosof
- & Mercedes Pascual
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| Open AccessPlasmepsin II–III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum
Piperaquine (PPQ) resistance of Plasmodium is an increasing problem. Here, Bopp et al. find a bimodal dose−response curve of Cambodian isolates exposed to PPQ, with the area under the curve correlating with in vitro PPQ resistance, and show the importance of Plasmepsin II–III copy number to PPQ resistance.
- Selina Bopp
- , Pamela Magistrado
- & Sarah K. Volkman
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| Open AccessA cryptic cycle in haematopoietic niches promotes initiation of malaria transmission and evasion of chemotherapy
Malaria transmission is effected by intra-erythrocytic parasites that commit to sexual development and form gametocytes. Here, the authors show that early reticulocytes in the major sites of haematopoiesis establish a cryptic asexual cycle; this cycle is characterised by early preferential commitment to gametocytogenesis, which initiates malaria transmission and drug resistance.
- Rebecca S. Lee
- , Andrew P. Waters
- & James M. Brewer
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| Open AccessHost-mediated selection impacts the diversity of Plasmodium falciparum antigens within infections
Host immune responses exert selective pressure on Plasmodium falciparum. Here, the authors show that allele-specific immunity impacts the antigenic diversity of individual malaria infections. This process partially explains the extreme amino acid diversity of many parasite antigens and suggests that vaccines should account for allele-specific immunity.
- Angela M. Early
- , Marc Lievens
- & Daniel E. Neafsey
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| Open AccessStrong selection during the last millennium for African ancestry in the admixed population of Madagascar
The population of Madagascar arose from admixture of Austronesian and Bantu genetic backgrounds. Analyzing local ancestry in genomes of 700 Malagasy, Pierron et al. identify signals of recent positive selection for African ancestry in a region on chromosome 1 with implications for physiology and disease risk.
- Denis Pierron
- , Margit Heiske
- & Thierry Letellier
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| Open AccessLong-acting injectable atovaquone nanomedicines for malaria prophylaxis
Long-acting antimalarials could provide improved prophylaxis and treatment options in the field. Here, Bakshi et al. develop a long-acting injectable atovaquone nanomedicine that prevents malaria infection prophylactically for up to 4 weeks in mice with no evidence for generation of resistant parasites.
- Rahul P. Bakshi
- , Lee M. Tatham
- & Theresa A. Shapiro
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Article
| Open AccessMolecular definition of multiple sites of antibody inhibition of malaria transmission-blocking vaccine antigen Pfs25
Plasmodium falciparum protein Pfs25 is a promising malaria transmission blocking vaccine antigen. Here, Scally et al. determine the crystal structure of Pfs25 and identify antigenic sites that are recognized by transmission-blocking antibodies elicited in human immunoglobulin loci transgenic mice.
- Stephen W. Scally
- , Brandon McLeod
- & Jean-Philippe Julien
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| Open AccessHuman Cyclophilin B forms part of a multi-protein complex during erythrocyte invasion by Plasmodium falciparum
Invasion of red blood cells by Plasmodium falciparum is a complex process and relies on several receptor-ligand interactions. Here, the authors show that human cyclophilin B binds Plasmodium surface protein PfRhopH3 and that interruption of this interaction reduces invasion by 80%.
- Prem Prakash
- , Mohammad Zeeshan
- & Pawan Malhotra
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| Open AccessAssessing the impact of imperfect adherence to artemether-lumefantrine on malaria treatment outcomes using within-host modelling
Artemether lumefantrine is widely used for the treatment of uncomplicated malaria. The impact of imperfect patient adherence to the six-dose regimen is hard to assess. Using adherence data for unsupervised patients, the authors model how suboptimal adherence affects treatment outcomes.
- Joseph D. Challenger
- , Katia Bruxvoort
- & Lucy C. Okell
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Article
| Open AccessExamining the human infectious reservoir for Plasmodium falciparum malaria in areas of differing transmission intensity
Heterogeneity in the transmission potential of individual hosts is an important feature of malaria. Here, the authors perform a multi-regional study of the human infectious reservoir in malaria-endemic regions of Burkina Faso and Kenya.
- Bronner P. Gonçalves
- , Melissa C. Kapulu
- & Teun Bousema
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Article
| Open AccessProtein O-fucosylation in Plasmodium falciparum ensures efficient infection of mosquito and vertebrate hosts
The role of O-glycosylation in the malaria life cycle is largely unknown. Here, the authors identify a Plasmodium protein O-fucosyltransferase and show that it is important for normal trafficking of a subset of surface proteins, particularly CSP and TRAP, and efficient infection of mosquito and vertebrate hosts.
- Sash Lopaticki
- , Annie S. P. Yang
- & Justin A. Boddey
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| Open AccessAccurate immune repertoire sequencing reveals malaria infection driven antibody lineage diversification in young children
Somatic hypermutation of antibodies can occur in infants but are difficult to track. Here the authors present a new method called MIDCIRS for deep quantitative repertoire sequencing with few cells, and show infants as young as 3 months can expand antibody lineage complexity in response to malaria infection.
- Ben S. Wendel
- , Chenfeng He
- & Ning Jiang
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Article
| Open AccessA potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission
Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes.
- David A. Baker
- , Lindsay B. Stewart
- & Simon A. Osborne
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Article
| Open AccessA Plasmodium yoelii HECT-like E3 ubiquitin ligase regulates parasite growth and virulence
Many strains of Plasmodium differ in virulence, but factors that control these distinctions are not known. Here the authors comparatively map virulence loci using the offspring from a P. yoelii YM and N67 genetic cross, and identify a putative HECT E3 ubiquitin ligase that may explain the variance.
- Sethu C. Nair
- , Ruixue Xu
- & Xin-zhuan Su
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| Open AccessAn exported protein-interacting complex involved in the trafficking of virulence determinants in Plasmodium-infected erythrocytes
Plasmodium-infected red blood cells export virulence factors, such asPfEMP1, to the cell surface. Here, the authors identify a protein complex termed EPIC that interacts with PfEMP1 during export, and they show that knockdown of an EPIC component affects parasite virulence.
- Steven Batinovic
- , Emma McHugh
- & Leann Tilley
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Article
| Open AccessPfCDPK1 mediated signaling in erythrocytic stages of Plasmodium falciparum
Calcium dependent protein kinase 1 (CDPK1) plays an important role in asexual development of Plasmodium falciparum. Using phosphoproteomics and conditional knockdown of CDPK1, the authors here identify CDPK1 substrates and a cross-talk between CDPK1 and PKA, and show the role of CDPK1 in parasite invasion.
- Sudhir Kumar
- , Manish Kumar
- & Pushkar Sharma
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| Open AccessA tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance
Artemisinin-resistantPlasmodium is an increasing problem. Here, using a medicinal chemistry programme, the authors identify a tetraoxane-based drug candidate that shows no cross-resistance with an artemisinin-resistant strain (PfK13-C580Y) and is efficient in Plasmodiummouse models.
- Paul M. O’Neill
- , Richard K. Amewu
- & Stephen A. Ward