Article
|
Open Access
Featured
-
-
Article
| Open AccessDynamic methylation of histone H3K18 in differentiating Theileria parasites
Post-translational modifications (PTM) of histones are important for epigenetic regulation in mammals. Here, Cheeseman et al. report dynamic changes in H3K18 PTM during the differentiation stages of Theileria parasites and they identify a SET-domain methyltransferase (TaSETup1) as the relevant enzyme promoting this modification.
- Kevin Cheeseman
- , Guillaume Jannot
- & Jonathan B. Weitzman
-
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
-
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
-
Article
| Open AccessCryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding
In placental malaria, interactions between parasite protein VAR2CSA and human glycosaminoglycan chondroitin sulfate A (CS) sequesters infected red blood cells in the placenta. Here, the authors provide cryo-EM structures of VAR2CSA and placental CS, identifying molecular interactions that could guide design of placental malaria vaccines.
- Kaituo Wang
- , Robert Dagil
- & Ali Salanti
-
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
-
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
-
Article
| Open AccessA human monoclonal antibody blocks malaria transmission and defines a highly conserved neutralizing epitope on gametes
Vaccines that interrupt malaria transmission will be important tools for malaria elimination. Here the authors identify a human monoclonal antibody from Pfs230 vaccinated individuals that blocks transmission of Plasmodium falciparum to mosquitoes in a complement-dependent manner and reacts with gamete surface.
- Camila H. Coelho
- , Wai Kwan Tang
- & Patrick E. Duffy
-
Article
| Open AccessMechanisms and targets of Fcγ-receptor mediated immunity to malaria sporozoites
Antibodies plays critical roles in the adaptive immune response to infectious agents including malaria. Here the authors defined antibody interactions with -Fcγ-receptors expressed on immune cells with sporozoites of Plasmodium falciparum, and identified specific target epitopes of antibodies.
- Gaoqian Feng
- , Bruce D. Wines
- & James G. Beeson
-
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
-
Article
| Open AccessNaturally acquired blocking human monoclonal antibodies to Plasmodium vivax reticulocyte binding protein 2b
Plasmodium vivax reticulocyte binding protein 2b (PvRBP2b) is important for invasion of reticulocytes and PvRBP2b antibodies correlate with protection. Here, Chan et al. isolate and characterize anti-PvRBP2b human monoclonal antibodies and describe mechanisms by which these antibodies inhibit invasion.
- Li-Jin Chan
- , Anugraha Gandhirajan
- & Wai-Hong Tham
-
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
-
Article
| Open Access20S proteasomes secreted by the malaria parasite promote its growth
Plasmodium falciparum secretes extracellular vesicles (EVs) while growing inside red blood cells (RBCs). Here the authors show that these EVs contain assembled and functional 20S proteasome complexes that remodel the cytoskeleton of naïve human RBCs, priming the RBCs for parasite invasion.
- Elya Dekel
- , Dana Yaffe
- & Neta Regev-Rudzki
-
Article
| Open AccessStructural and biophysical correlation of anti-NANP antibodies with in vivo protection against P. falciparum
The most advanced P. falciparum circumsporozoite protein (PfCSP)-based malaria vaccine confers partial protection. Here, Pholcharee et al. present crystal structures, binding affinities/kinetics, and in vivo protection of 8 anti-NANP antibodies to understand in vivo protection of PfCSP-targeting antibodies.
- Tossapol Pholcharee
- , David Oyen
- & Ian A. Wilson
-
Article
| Open AccessFast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice
Glycolytic enzymes are challenging drug targets due to their highly conserved active sites and phosphorylated substrates. Here, the authors identify fast acting allosteric inhibitors of Trypanosoma brucei phosphofructokinase that block trypanosome glycolysis and provide cure evidence in murine model.
- Iain W. McNae
- , James Kinkead
- & Malcolm D. Walkinshaw
-
Article
| Open AccessMagneto-optical diagnosis of symptomatic malaria in Papua New Guinea
Here Arndt et al. establish rotating-crystal magneto-optical detection (RMOD) as a near-point-of-care diagnostic tool for malaria detection and report a sensitivity and specificity of 82% and 84%, respectively, as validated by analyzing a clinical population in a high transmission setting in Papua New Guinea.
- L. Arndt
- , T. Koleala
- & S. Karl
-
Article
| Open AccessGenotyping cognate Plasmodium falciparum in humans and mosquitoes to estimate onward transmission of asymptomatic infections
Asymptomatic malaria infections contribute to transmission. Here, Sumner et al. infer participant-to-mosquito transmission by sampling naturally-fed mosquitoes from households in Western Kenya and find that asymptomatic infections more than double the odds of transmission to a mosquito compared to symptomatic infections.
- Kelsey M. Sumner
- , Elizabeth Freedman
- & Steve M. Taylor
-
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
-
Article
| Open AccessStructural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines
Bicyclic azetidine inhibitors are promising antimalarials that target the Plasmodium cytosolic phenylalanine tRNAsynthetase (cFRS). Here, Sharma et al. provide the biochemical and structural basis of its mechanism using co-crystal structure of PvcFRS with BRD1389.
- Manmohan Sharma
- , Nipun Malhotra
- & Amit Sharma
-
Article
| Open AccessMultistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box
Here, Reader et al. screen the Medicines for Malaria Venture Pandemic Response Box in parallel against Plasmodiumasexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. They identify two potent transmission-blocking drugs: a histone demethylase inhibitor ML324 and the antitubercular SQ109.
- Janette Reader
- , Mariëtte E. van der Watt
- & Lyn-Marié Birkholtz
-
Article
| 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
-
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
-
Article
| Open AccessSingle-cell atlas of the first intra-mammalian developmental stage of the human parasite Schistosoma mansoni
Schistosomes undergo several develepmental stages during infection of humans. Here, the authors perform single-cell RNA sequencing on the earliest intra-mammalian stage of Schistosoma mansoni and generate a comprehensive cell-type atlas for this human parasite.
- Carmen Lidia Diaz Soria
- , Jayhun Lee
- & Matthew Berriman
-
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
-
Article
| Open AccessNeonicotinoid Clothianidin reduces honey bee immune response and contributes to Varroa mite proliferation
Pesticides could increase bees’ susceptibility to parasites, but the nature of this interaction has been unclear. Here the authors show that the pesticide Clothianidin reduces the wound healing immune response in bees, allowing the ectoparasitic Varroa mites to consume more bee hemolymph and amplify reproduction.
- Desiderato Annoscia
- , Gennaro Di Prisco
- & Francesco Pennacchio
-
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
-
Article
| Open AccessGenome-wide screens identify Toxoplasma gondii determinants of parasite fitness in IFNγ-activated murine macrophages
Using a genome-wide CRISPR screen, the authors here identify Toxoplasma genes that counteract the anti-parasitic activity of interferon gamma in murine macrophages. One of these genes, dense granule protein GRA45, is critical for the trafficking of GRA effectors and affects virulence in mice.
- Yifan Wang
- , Lamba Omar Sangaré
- & Jeroen P. J. Saeij
-
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
-
Article
| Open AccessEntamoeba and Giardia parasites implicated as hosts of CRESS viruses
Metagenomics allows virus genome discovery, but the viral hosts are often not identified. Here, Kinsella et al. use recombination events between virus genomes, statistical association of viruses to hosts in clinical samples, and analysis of endogenous viral elements in host genomes to identify probable hosts of three CRESS virus families.
- Cormac M. Kinsella
- , Aldert Bart
- & Lia van der Hoek
-
Article
| Open AccessCaspase-8 mediates inflammation and disease in rodent malaria
Inflammasome activation plays a role in malaria pathogenesis, but details aren’t well understood. Here, the authors show that caspase-8 is a central mediator of systemic inflammation in rodent malaria and that monocytes from malaria patients express active caspases-1, -4 and -8.
- Larissa M. N. Pereira
- , Patrícia A. Assis
- & Ricardo T. Gazzinelli
-
Article
| Open AccessAnalysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention
Plasmodium infection activates signaling pathways in a-nucleated erythrocytes. Here, Adderley et al. use a comprehensive antibody microarray to show that infection extensively modulates host cell signalling and that the host receptor tyrosine kinase c-MET supports Plasmodium falciparum proliferation.
- Jack D. Adderley
- , Simona John von Freyend
- & Christian Doerig
-
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
-
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
-
Article
| Open AccessGasdermin-D-dependent IL-1α release from microglia promotes protective immunity during chronic Toxoplasma gondii infection
Control over T. gondii infection in the brain involves microglial cells, but how these cells execute this control is not clear. Here the authors show that unlike IL-1β dominant macrophages, microglia are primed for gasdermin-D-dependent IL-1α production that is critical for protection against T. gondii infection.
- Samantha J. Batista
- , Katherine M. Still
- & Tajie H. Harris
-
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
-
Article
| Open AccessA second generation leishmanization vaccine with a markerless attenuated Leishmania major strain using CRISPR gene editing
Here, the authors engineer an attenuated knock-out Leishmania (LmCen−/−) vaccine that is safe in immunocompromised mice and induces an immune response and protection similar to leishmanization with wild-type Leishmania. Since LmCen−/− is antibiotic resistant marker free, it is a candidate for clinical development.
- Wen-Wei Zhang
- , Subir Karmakar
- & Hira L. Nakhasi
-
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
-
Article
| Open AccessPlasma-derived extracellular vesicles from Plasmodium vivax patients signal spleen fibroblasts via NF-kB facilitating parasite cytoadherence
Extracellular vesicles (EVs) in plasma can affect pathogenesis of parasites, but details remain unclear. Here, Toda et al. characterize plasma-derived EVs from Plasmodium vivax patients and show that PvEVs are preferentially taken up by human spleen fibroblasts, facilitating parasite cytoadherence.
- Haruka Toda
- , Miriam Diaz-Varela
- & Hernando A. del Portillo
-
Article
| Open AccessSex chromosome evolution in parasitic nematodes of humans
Many nematode worms, including Caenorhabditis elegans have XX/XO sex determination, while other species have XY. The authors use a new genome assembly of the filarial parasite Brugia malayi and published data to show that nematode sex chromosome evolution is highly plastic.
- Jeremy M. Foster
- , Alexandra Grote
- & Elodie Ghedin
-
Article
| Open AccessCD8+ regulatory T cells are critical in prevention of autoimmune-mediated diabetes
Helminth infections are associated with a reduction in inflammatory pathology in rodent models of type 1 diabetes. Here, the authors show patient data and that trehalose (produced by H. polygyrus) can alter the microbiome of mice, inducing regulatory CD8+ T cells and reducing susceptibility to autoimmune diabetes.
- Chikako Shimokawa
- , Tamotsu Kato
- & Hajime Hisaeda
-
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
-
Article
| Open AccessDistinct roles for H4 and H2A.Z acetylation in RNA transcription in African trypanosomes
Histone modification and deposition are key regulators of transcription. Here, Kraus et al. provide a quantitative histone acetylome for Trypanosoma brucei, identify histone modifications enriched at transcription start sites, and show how H4 and H2A.Z acetylation affect histone deposition and transcription in trypanosomes.
- Amelie J. Kraus
- , Jens T. Vanselow
- & T. Nicolai Siegel
-
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
-
Article
| Open AccessA receptor for the complement regulator factor H increases transmission of trypanosomes to tsetse flies
African trypanosome infections can persist for years, but immune evasion mechanisms are not fully understood. Here, Macleod et al. identify a trypanosome receptor for mammalian factor H, a negative regulator of the alternative complement pathway, that increases parasite transmission to tsetse flies.
- Olivia J. S. Macleod
- , Jean-Mathieu Bart
- & Mark Carrington
-
Article
| Open AccessAmplification of Duffy binding protein-encoding gene allows Plasmodium vivax to evade host anti-DBP humoral immunity
Duffy binding protein (DBP) of Plasmodium vivax is important for invasion and is a potential vaccine candidate. Here, the authors show that PvDBP gene amplification protects P vivax in vitro against invasion inhibitory human monoclonal antibodies and is associated to infection of patients with PvDBP binding inhibitory antibodies.
- Jean Popovici
- , Camille Roesch
- & Benoit Witkowski
-
Article
| Open AccessVariant antigen diversity in Trypanosoma vivax is not driven by recombination
Trypanosoma rely on variant surface glycoprotein (VSG) to escape host immunity, but mechanisms generating antigenic diversity of VSG are poorly understood. Here, Silva-Pereira et al. show that T. vivax has a limited antigenic repertoire compared to T. brucei and that recombination plays little role in diversifying T. vivax VSG sequences.
- Sara Silva Pereira
- , Kayo J. G. de Almeida Castilho Neto
- & Andrew P. Jackson
-
Article
| Open AccessAfrican-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin
A polymorphism in human TP53 (P47S) that predominantly exists in individuals of African descent affects ferroptosis. Here, the authors show that this results in iron accumulation in macrophages leading to more productive infection by intracellular bacteria but improved anti-inflammatory response to the malarial toxin hemozoin.
- Kumar Sachin Singh
- , Julia I-Ju Leu
- & Farokh Dotiwala
-
Article
| Open AccessMetabolic balancing by miR-276 shapes the mosquito reproductive cycle and Plasmodium falciparum development
Plasmodium growth is adapted to the reproductive cycle of mosquitoes, but underlying mechanisms are unclear. Here, Lampe et al. show that the blood-meal induced miR-276 balances the termination of the mosquito amino acid catabolism and egg development, providing nutrients for Plasmodium sporozoite development.
- Lena Lampe
- , Marius Jentzsch
- & Elena A. Levashina
-
Article
| Open AccessCoupling chemical mutagenesis to next generation sequencing for the identification of drug resistance mutations in Leishmania
Here, Bhattacharya et al. chemically mutagenize Leishmania and identify genes associated with resistance to miltefosine and paromomycin by next generation sequencing. The study shows that a protein kinase (CDPK1) can mediate resistance to paromomycin by affecting translation.
- Arijit Bhattacharya
- , Philippe Leprohon
- & Marc Ouellette
-
Article
| Open AccessHigh-resolution micro-epidemiology of parasite spatial and temporal dynamics in a high malaria transmission setting in Kenya
Here, Nelson et al. use amplicon next-generation sequencing of two P. falciparum polymorphic gene regions to investigate the genetic similarity of parasite populations across time and space in a pediatric cohort in Kenya. They identify both micro- and macro-scale structuring of malaria parasites in this high-transmission setting, which could inform future intervention strategies.
- Cody S. Nelson
- , Kelsey M. Sumner
- & Wendy P. O’Meara