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| Open AccessTransgenic Anopheles mosquitoes expressing human PAI-1 impair malaria transmission
Plasmodium gametes and sporozoites activate surface-bound plasminogen to plasmin that degrades extracellular matrix barriers, therewith facilitating parasite motility in mosquitoes and mammalian hosts. To control malaria transmission, Pascini et al. generate Anopheles stephensi transgenic mosquitoes constitutively secreting human plasminogen activator inhibitor 1 in midgut and/or saliva which leads to inhibition of plasminogen activation and a reduction in oocyst intensity, infection prevalence, and transmission.
- Tales V. Pascini
- , Yeong Je Jeong
- & Joel Vega-Rodríguez
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Article
| Open AccessFunctional genomics of RAP proteins and their role in mitoribosome regulation in Plasmodium falciparum
The function of RNA-binding domain abundant in Apicomplexans (RAP) protein family members is largely unknown. Here, using high-throughput functional genomics, including metabolomics, Hollin et al. characterize two RAP proteins that are essential for Plasmodium falciparum survival and control mitochondrial rRNAs.
- Thomas Hollin
- , Steven Abel
- & Karine G. Le Roch
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Article
| Open AccessIn vitro maturation of Toxoplasma gondii bradyzoites in human myotubes and their metabolomic characterization
Bradyzoites are a quiescent form of Toxoplasma gondii enclosed in cysts during chronic infections. Here, Christiansen et al. develop a human myotube-based in vitro culture model of cysts that are infectious to mice and characterize their metabolism in comparison to fast replicating tachyzoites.
- Céline Christiansen
- , Deborah Maus
- & Martin Blume
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Article
| Open AccessCyclic AMP signalling and glucose metabolism mediate pH taxis by African trypanosomes
African trypanosomes collectively move in a process called social motility. Here, the authors show that procyclic forms acidify their environment as a consequence of glucose metabolism, generating pH gradients by diffusion that are sensed via cyclic AMP signalling. Parasite mutants defective in cAMP signaling are inhibited in fly infection.
- Sebastian Shaw
- , Sebastian Knüsel
- & Isabel Roditi
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Article
| Open AccessPantothenate biosynthesis is critical for chronic infection by the neurotropic parasite Toxoplasma gondii
Coenzyme A (CoA) is an essential metabolite found in all organisms and its synthesis involves five conserved enzymatic steps and uses pantothenate (Pan) as a precursor. Here, Lunghi et al. examine the Pan synthesis pathway in Toxoplasma gondii and find that Pan is crucial for the establishment of chronic but not acute infection.
- Matteo Lunghi
- , Joachim Kloehn
- & Dominique Soldati-Favre
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Article
| Open AccessAn assembly of nuclear bodies associates with the active VSG expression site in African trypanosomes
A Variant Surface Glycoprotein (VSG) coat protects bloodstream form T. brucei. Applying super-resolution microscopy Budzak et al. characterize a set of nuclear bodies, which associate with the active expression site in bloodstream form T. brucei and highlight the importance of trans-splicing for transcription of VSG.
- James Budzak
- , Robert Jones
- & Gloria Rudenko
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Article
| Open AccessPlasmodium sporozoite phospholipid scramblase interacts with mammalian carbamoyl-phosphate synthetase 1 to infect hepatocytes
After transmission of Plasmodium sporozoites from infected mosquitoes, parasites first infect hepatocytes. Here, Cha et al. identify a sporozoite ligand (phospholipid scramblase) and the hepatocytic receptor (carbamoyl-phosphate synthetase 1) as relevant for hepatocyte invasion and show that an antibody to hepatocyte-binding peptide 1 (HP1), which structurally mimics the sporozoite ligand, partially protects mice from infection.
- Sung-Jae Cha
- , Min-Sik Kim
- & Marcelo Jacobs-Lorena
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Article
| Open AccessIn situ ultrastructures of two evolutionarily distant apicomplexan rhoptry secretion systems
The rhoptry is an apical secretory organelle of apicomplexan parasites that is essential for host cell invasion. Here, Mageswaran et al. provide in situ ultrastructures of rhoptries from two pathogens, revealing a conserved architecture including luminal filaments and a distinct docking mechanism.
- Shrawan Kumar Mageswaran
- , Amandine Guérin
- & Yi-Wei Chang
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Article
| Open AccessComposition and stage dynamics of mitochondrial complexes in Plasmodium falciparum
Applying complexome profiling, Evers et al. unravel the composition of mitochondrial oxidative phosphorylation complexes in P. falciparum asexual and sexual blood stages. Abundance of these complexes differs between both stages, supporting the hypothesis that a mitochondrial metabolic switch is central to gametocyte development and functioning.
- Felix Evers
- , Alfredo Cabrera-Orefice
- & Taco W. A. Kooij
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Article
| Open AccessStructural insights into an atypical secretory pathway kinase crucial for Toxoplasma gondii invasion
Host cell invasion by Toxoplasma gondii depends on the heavily phosphorylated RON complex, but the relevance and regulation of these modifications are not understood. Here, the authors identify the kinase RON13 as a key virulence factor, determine its structure and show that it phosphorylates the RON complex.
- Gaëlle Lentini
- , Rouaa Ben Chaabene
- & Dominique Soldati-Favre
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Article
| Open Access4D analysis of malaria parasite invasion offers insights into erythrocyte membrane remodeling and parasitophorous vacuole formation
Here, Geoghegan, Evelyn et al. provide a lattice light-sheet microscopy based 4D imaging pipeline to quantitatively investigate Plasmodium spp. invasion and show that the nascent parasitophorous vacuole is predominantly formed from host’s erythrocyte membrane and undergoes continuous remodeling throughout invasion.
- Niall D. Geoghegan
- , Cindy Evelyn
- & Kelly L. Rogers
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Article
| Open AccessA single-cell atlas of Plasmodium falciparum transmission through the mosquito
Here the authors use single-cell RNA-seq to profile the transmission stages of the human malaria parasite Plasmodium falciparum as it progresses through the Anopheles mosquito. They highlight unique patterns of gene usage throughout this development and identify potential pleiotropic genes that function at multiple life cycle stages.
- Eliana Real
- , Virginia M. Howick
- & Mara K. N. Lawniczak
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Article
| Open AccessCryo-EM structure of cortical microtubules from human parasite Toxoplasma gondii identifies their microtubule inner proteins
Cortical microtubules (MTs) in Apicomplexa are specialized MTs involved in maintaining the parasite’s shape and are, as such, unusually stable. Here, cryo-EM analysis of cortical MTs from Toxoplasma gondii offers insight into the mechanism of their stabilization by three bona fide microtubule inner proteins.
- Xiangli Wang
- , Yong Fu
- & Rui Zhang
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Article
| Open AccessToxoplasma LIPIN is essential in channeling host lipid fluxes through membrane biogenesis and lipid storage
Apicomplexa generate essential lipids as combination of host fatty acids and de novo synthesized within the apicoplast. Here, the authors identify a phosphatidic acid phosphatase in Toxoplasma gondii, TgLIPIN, as central for controlled lipid synthesis and define the host-scavenged lipidome.
- Sheena Dass
- , Serena Shunmugam
- & Cyrille Y. Botté
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Article
| Open AccessHigher gametocyte production and mosquito infectivity in chronic compared to incident Plasmodium falciparum infections
In this longitudinal study of an incident (new infections) and chronic (asymptomatic infections) cohort of Plasmodium falciparum infection in children in Burkina Faso, the authors show higher gametocyte production and mosquito infectivity in chronic infections.
- Aissata Barry
- , John Bradley
- & Teun Bousema
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Article
| Open AccessPlasmodium vivax infection compromises reticulocyte stability
During Plasmodium intra-erythrocytic developmental, parasites compromise the structural integrity of host red-blood cells. Here, Clark et al. develop a flow cytometric osmotic stability assay to show that P. vivax infection destabilizes host reticulocytes, which are less stable than P. falciparum-infected normocytes.
- Martha A. Clark
- , Usheer Kanjee
- & Manoj T. Duraisingh
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Article
| Open AccessSystematic functional analysis of Leishmania protein kinases identifies regulators of differentiation or survival
Protein kinases are fundamental in cellular signalling required for Leishmania survival throughout the life cycle. Here, Baker and Catta-Preta et al. report on a kinome-wide functional study in Leishmania mexicana to define protein kinases with roles in life cycle transition.
- N. Baker
- , C. M. C. Catta-Preta
- & J. C. Mottram
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Article
| Open AccessArtemisinin-resistant K13 mutations rewire Plasmodium falciparum’s intra-erythrocytic metabolic program to enhance survival
The emergence and spread of artemisinin resistance has compromised antimalarial efficacy. Here, Mok et al. apply quantitative transcriptomics, proteomics, and metabolomics to provide evidence that K13 mutations alter multiple aspects of the parasite’s intra-erythrocytic development to enhance survival following artemisinin treatment.
- Sachel Mok
- , Barbara H. Stokes
- & David A. Fidock
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| Open AccessCharacterization of a new Leishmania major strain for use in a controlled human infection model
Controlled human infection models (CHIMs) provide a pathway for accelerating vaccine development. Here, the authors describe the isolation, characterization, and GMP manufacture of a clinical Leishmania major strain to be used as a resource for CHIM studies of sand fly transmitted cutaneous leishmaniasis.
- Helen Ashwin
- , Jovana Sadlova
- & Paul M. Kaye
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Article
| Open AccessTgAP2IX-5 is a key transcriptional regulator of the asexual cell cycle division in Toxoplasma gondii
The control of the proper timing of emergence of apicomplexan parasite daughter cells during replication is crucial for their proliferation. Here, Khelifa et al. identify a key transcriptional regulator in the model Apicomplexa Toxoplasma gondii, which regulates the expression of transcription factors necessary for completion of the budding cycle.
- Asma S. Khelifa
- , Cecilia Guillen Sanchez
- & Mathieu Gissot
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Article
| Open AccessThe transcriptome of circulating sexually committed Plasmodium falciparum ring stage parasites forecasts malaria transmission potential
Malaria gametocytes are sexual-stage parasites transmitted from mammalian host’s blood back to their insect vector. Here, Prajapati et al. identify gametocyte-committed ring-stage biomarkers allowing to forecast malaria transmission potential.
- Surendra K. Prajapati
- , Ruth Ayanful-Torgby
- & Kim C. Williamson
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Article
| Open AccessPlasmodium translocon component EXP2 facilitates hepatocyte invasion
While the role of Plasmodium EXP2 protein as translocon component of blood stage parasites is established, its functional role in liver stage parasites remains unclear. Here, Mello-Vieira et al. reveal that EXP2 pore-forming activity induces hepatocyte membrane repair and hence is critical for hepatocyte invasion.
- João Mello-Vieira
- , Francisco J. Enguita
- & Maria M. Mota
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Article
| Open AccessGenetic screens reveal a central role for heme metabolism in artemisinin susceptibility
Artemisinin (ART) resistance poses a problem for malaria elimination. Here, the authors perform genome-wide CRISPR screens in Toxoplasma gondii and identify that the putative transporter Tmem14c and mitochondrial heme metabolism, through mitochondrial protease DegP2, affect ART susceptibility.
- Clare R. Harding
- , Saima M. Sidik
- & Sebastian Lourido
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Article
| Open AccessThe natural function of the malaria parasite’s chloroquine resistance transporter
Plasmodium falciparum chloroquine resistance transporter (PfCRT) mediates multidrug resistance, but its natural function remains unclear. Here, Shafik et al. show that PfCRT transports host-derived peptides of 4-11 residues but not other ions or metabolites, and that drug-resistance-conferring PfCRT mutants have reduced peptide transport.
- Sarah H. Shafik
- , Simon A. Cobbold
- & Rowena E. Martin
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Article
| Open AccessContacting domains segregate a lipid transporter from a solute transporter in the malarial host–parasite interface
While membrane contact sites between intracellular organelles are abundant, little is known about the contacts between membranes that delimit extracellular junctions within cells, such as intracellular parasites. Here authors demonstrate the segregation of a lipid transporter from a solute transporter in the malarial host-parasite interface.
- Matthias Garten
- , Josh R. Beck
- & Joshua Zimmerberg
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Article
| Open AccessCo-option of Plasmodium falciparum PP1 for egress from host erythrocytes
Plasmodium protein phosphatase PP1 is essential for the asexual proliferation of malaria parasites. Here the authors show that PP1 regulates egress of parasites from host red blood cells, integrating parasite intrinsic pathways with environmental signals for release into the bloodstream.
- Aditya S. Paul
- , Alexandra Miliu
- & Manoj T. Duraisingh
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Article
| Open AccessMalaria parasites regulate intra-erythrocytic development duration via serpentine receptor 10 to coordinate with host rhythms
The mechanism underlying periodicity of Plasmodium’s intra-erythrocytic developmental cycle (IDC) is unclear. Here, Subudhi et al. show that serpentine receptor 10 (SR10) plays a role in regulating the schedule of the IDC in line with the timing of host daily rhythms.
- Amit K. Subudhi
- , Aidan J. O’Donnell
- & Arnab Pain
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Article
| Open AccessA microsporidian impairs Plasmodium falciparum transmission in Anopheles arabiensis mosquitoes
Mircobial symbionts of mosquitoes can affect transmission of human pathogens. Here, Herren et al. identify a microsporidian symbiont in Anopheles gambiae that impairs transmission without affecting mosquito fecundity or survival.
- Jeremy K. Herren
- , Lilian Mbaisi
- & Steven P. Sinkins
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Article
| Open AccessAn intracellular membrane protein GEP1 regulates xanthurenic acid induced gametogenesis of malaria parasites
Mosquito-derived xanthurenic acid (XA) is a trigger for gametogenesis of Plasmodium parasites. Here the authors show that the putative amino acid transporter GEP1 is required for XA-stimulated gametogenesis in Plasmodium yoelii and that it interacts with guanylyl cyclase α (GCα), a cGMP synthesizing enzyme in gametocytes.
- Yuanyuan Jiang
- , Jun Wei
- & Jing Yuan
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Article
| Open AccessPfCERLI1 is a conserved rhoptry associated protein essential for Plasmodium falciparum merozoite invasion of erythrocytes
Rhoptries are essential organelles for invasion of erythrocytes by Plasmodium. Here, the authors characterize the rhoptry-associated protein CERLI1 using quantitative super-resolution microscopy, showing that it is important for parasite invasion and secretion of rhoptry proteins including vaccine antigens.
- Benjamin Liffner
- , Sonja Frölich
- & Danny W. Wilson
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Article
| Open AccessTranscriptomics and proteomics reveal two waves of translational repression during the maturation of malaria parasite sporozoites
Here, the authors report transcriptomes and proteomes of oocyst sporozoite and salivary gland sporozoite stages in rodent-infectious Plasmodium yoelii parasites and human infectious Plasmodium falciparum parasites and define two waves of translational repression during sporozoite maturation.
- Scott E. Lindner
- , Kristian E. Swearingen
- & Stefan H. I. Kappe
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Article
| Open AccessAdaptation of Plasmodium falciparum to humans involved the loss of an ape-specific erythrocyte invasion ligand
Here, Proto et al. show that human infective Plasmodium falciparum isolates contain an inactivating mutation in the erythrocyte invasion associated gene PfEBA165, while homologues of ape-infective Laverania species are intact, and that expression of intact PfEBA165 is incompatible with parasite growth in human erythrocytes.
- William R. Proto
- , Sasha V. Siegel
- & Julian C. Rayner
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Article
| Open AccessA highly dynamic F-actin network regulates transport and recycling of micronemes in Toxoplasma gondii vacuoles
Replication of Toxoplasma gondii requires replication and distribution of essential organelles such as micronemes. Here, Periz et al. show that micronemes are recycled from the mother to the forming daughter cells using a highly dynamic F-actin network that supports multidirectional vesicle transport.
- Javier Periz
- , Mario Del Rosario
- & Markus Meissner
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Article
| Open AccessA lipid-binding protein mediates rhoptry discharge and invasion in Plasmodium falciparum and Toxoplasma gondii parasites
Plasmodium and Toxoplasma parasites rely on rhoptry exocytosis for invasion, but the underlying mechanism is not known. Here, Suarez et al. characterize rhoptry apical surface proteins (RASP) that localize to the rhoptry cap and bind charged lipids, and are essential for rhoptry secretion and invasion.
- Catherine Suarez
- , Gaëlle Lentini
- & Maryse Lebrun
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Article
| Open AccessMonoallelic expression and epigenetic inheritance sustained by a Trypanosoma brucei variant surface glycoprotein exclusion complex
Monoallelic expression of variant surface glycoprotein genes (VSGs) is essential for immune evasion by Trypanosoma brucei. Here, Faria et al. show that the VEX protein complex controls VSG allelic exclusion, and that CAF‐1 sustains inheritance of the VEX‐complex in association with the active VSG.
- Joana Faria
- , Lucy Glover
- & David Horn
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Article
| Open AccessInherent biomechanical traits enable infective filariae to disseminate through collecting lymphatic vessels
Stimuli affecting migration of filaria in host tissues are unclear. Using in situ imaging, Kilarski et al. here show that universal adaptations of nematodes allow Litomosoides sigmodontis infective larvae to mechanically break into pre-collecting lymphatics and follow the direction of flow towards the lymph node.
- Witold W. Kilarski
- , Coralie Martin
- & Melody A. Swartz
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Article
| Open AccessAn essential contractile ring protein controls cell division in Plasmodium falciparum
Schizogony is essential for blood stage infection of Plasmodium parasites and produces several daughter cells. Here, Rudlaff et al. identify PfCINCH and interacting proteins as essential components of the basal complex required to establish daughter cell boundaries.
- Rachel M. Rudlaff
- , Stephan Kraemer
- & Jeffrey D. Dvorin
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Article
| Open AccessThe parasitic worm product ES-62 normalises the gut microbiota bone marrow axis in inflammatory arthritis
Gastrointestinal infection with parasitic helminths can protect against mucosal diseases via impacting on the microbiome. Here the authors show that ES-62, a product secreted by a tissue-resident helminth modulates the host gut microbiome to protect against inflammatory arthritis in a mouse model.
- James Doonan
- , Anuradha Tarafdar
- & William Harnett
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Article
| Open AccessNucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma
Protein kinase A (PKA) is typically activated by cAMP. Here, Bachmaier et al. show that PKA of Trypanosoma is activated by nucleoside-related ligands, explain the ligand selectivity swap by a co-crystal structure of trypanosome PKAR, and identify potential downstream targets by phosphoproteomics.
- Sabine Bachmaier
- , Yuri Volpato Santos
- & Michael Boshart
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Article
| Open AccessFlagellar cAMP signaling controls trypanosome progression through host tissues
Trypanosoma brucei probably relies on chemotactic signals for movement through tsetse fly tissues, but the molecular basis is unknown. Here, the authors show that flagellar cAMP signaling is required for traversal of the peritrophic matrix and that, without it, parasites are trapped in the midgut lumen.
- Sebastian Shaw
- , Stephanie F. DeMarco
- & Kent L. Hill
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Article
| Open AccessAlveolar proteins stabilize cortical microtubules in Toxoplasma gondii
Cortical microtubules of Toxoplasma gondii are exceptionally stable, but it isn’t known how they are anchored along membranes. Here, Harding et al. show that GAPM proteins localize to the inner membrane complex and are essential for maintaining the structural stability of parasites.
- Clare R. Harding
- , Matthew Gow
- & Sebastian Lourido
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Article
| Open AccessPlasmodium vivax transcriptomes reveal stage-specific chloroquine response and differential regulation of male and female gametocytes
Plasmodium vivax biology is not well understood, due to a lack of in vitro culture systems and difficulties associated with studying clinical blood samples. Here, Kim et al. use gene expression profiles from P. vivax infected patient blood and show stage-specific chloroquine response and differential regulation of male and female gametocytes.
- Adam Kim
- , Jean Popovici
- & David Serre
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Article
| Open AccessPentatricopeptide repeat poly(A) binding protein KPAF4 stabilizes mitochondrial mRNAs in Trypanosoma brucei
Polyadenylation stabilizes edited mitochondrial mRNAs in Trypanosoma brucei, but the involved poly(A) binding protein is unknown. Here, Mesitov et al. show that a pentatricopeptide repeat factor KPAF4 binds to A-tail and prevents exonucleolytic degradation as well as translation of incompletely edited mRNAs.
- Mikhail V. Mesitov
- , Tian Yu
- & Inna Aphasizheva
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Article
| Open AccessA tRNA half modulates translation as stress response in Trypanosoma brucei
Trypanosoma brucei mainly relies on translational regulation to adjust gene expression, but details are unclear. Here the authors show that, under stress conditions, tRNAThr half level increases, associates with ribosomes and polysomes, and stimulates protein synthesis by facilitating mRNA loading.
- Roger Fricker
- , Rebecca Brogli
- & Norbert Polacek
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Article
| 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 AccessEmerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine
Increasing resistance of Plasmodium falciparum strains to piperaquine (PPQ) in Southeast Asia is of concern and resistance mechanisms are incompletely understood. Here, Ross et al. show that mutations in the P. falciparum chloroquine resistance transporter are rapidly increasing in prevalence in Cambodia and confer resistance to PPQ.
- Leila S. Ross
- , Satish K. Dhingra
- & David A. Fidock
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Article
| 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 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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Article
| Open AccessA conserved ankyrin repeat-containing protein regulates conoid stability, motility and cell invasion in Toxoplasma gondii
Apicomplexan parasites such as Toxoplasma gondii possess a tubulin-rich structure called the conoid. Here, Long et al. identify a conoid protein that interacts with motor and structural proteins and is required for structural integrity of the conoid, parasite motility, and host cell invasion.
- Shaojun Long
- , Bryan Anthony
- & L. David Sibley