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| Open AccessDistinct evolution of type I glutamine synthetase in Plasmodium and its species-specific requirement
In a study looking to examine the functional significance of glutamine synthetase (GS), the authors show that in Plasmodium, GS has evolved as a distinct type I enzyme with unique biochemical and structural features that complement the parasite niche.
- Sourav Ghosh
- , Rajib Kundu
- & Viswanathan Arun Nagaraj
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Article
| Open AccessA PPP-type pseudophosphatase is required for the maintenance of basal complex integrity in Plasmodium falciparum
The authors discover a pseudophosphatase that is an essential component of the basal complex, a contractile ring required for cell division of the malaria parasite. Using a combination of genetics, biochemistry, and cell biology techniques, they demonstrate that the pseudophosphatase, PfPPP8, is critical for integrity and contraction of the basal complex.
- Alexander A. Morano
- , Rachel M. Rudlaff
- & Jeffrey D. Dvorin
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Article
| Open AccessMultiplexed ddPCR-amplicon sequencing reveals isolated Plasmodium falciparum populations amenable to local elimination in Zanzibar, Tanzania
Sequencing malaria parasites from low density infections in small amounts of dried blood is important for large-scale genomic surveillance. Here, the authors develop and validate a highly multiplexed droplet digital PCR-based amplicon deep sequencing assay and apply it to data from Zanzibar, Tanzania.
- Aurel Holzschuh
- , Anita Lerch
- & Cristian Koepfli
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Article
| Open AccessThe vacuolar iron transporter mediates iron detoxification in Toxoplasma gondii
Iron is essential to cells, however without correct storage can lead to cell damage. Aghabi et al. show that the vacuolar iron transporter (VIT) is required for iron storage in the parasite Toxoplasma gondii. They find VIT protects against iron toxicity and has a role in parasite virulence.
- Dana Aghabi
- , Megan Sloan
- & Clare R. Harding
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Article
| Open AccessStructural basis for DARC binding in reticulocyte invasion by Plasmodium vivax
Plasmodium vivax is one of the major causes of human malaria. To replicate, it must get inside human blood cells, in a processing requiring binding of the parasite PvDBP protein to the human DARC receptor. This study reveals how PvDBP binds to DARC and will guide future vaccine design.
- Re’em Moskovitz
- , Tossapol Pholcharee
- & Matthew K. Higgins
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Article
| Open AccessGeneration of a mutator parasite to drive resistome discovery in Plasmodium falciparum
The ability to evolve Plasmodium drug resistance in vitro is challenging and time consuming. Here, Kümpornsin et al. generated a Plasmodium falciparum parasite line with an elevated mutation rate by impairing the proof-reading activity of DNA polymerase, which results in a higher mutation rate, quick resistance development, and a lower inoculum than wild type to support the identification of new antimalarial targets and understand drug resistance mechanisms.
- Krittikorn Kümpornsin
- , Theerarat Kochakarn
- & Marcus C. S. Lee
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Article
| Open AccessEB1 decoration of microtubule lattice facilitates spindle-kinetochore lateral attachment in Plasmodium male gametogenesis
EB are conserved microtubule (MT) plus-end binding proteins. Here, Yang et al. report that Plasmodium EB1 possesses distinct MT-lattice affinity and decorates the full-length of spindle MTs. Gene deletion impairs the spindle-kinetochore lateral attachment, leading to anucleated male gametes.
- Shuzhen Yang
- , Mengya Cai
- & Jing Yuan
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Article
| Open AccessPlasmodium falciparum has evolved multiple mechanisms to hijack human immunoglobulin M
Malaria parasites use various molecular tactics to hijack IgM antibodies and escape the human immune system.
- Chenggong Ji
- , Hao Shen
- & Junyu Xiao
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Article
| Open AccessTranslational reprogramming as a driver of antimony-drug resistance in Leishmania
Leishmania is a unicellular protozoan that has limited transcriptional control. Here, the authors show that translational control is a major mechanism of antimony drug resistance in Leishmania. They observe a dramatic translatome reprogramming during development of resistance to the drug and report translational control as a major driver of antimony-resistant phenotypes.
- Sneider Alexander Gutierrez Guarnizo
- , Elena B. Tikhonova
- & Zemfira N. Karamysheva
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Article
| Open AccessAntibodies to variable surface antigens induce antigenic variation in the intestinal parasite Giardia lamblia
Antigenic variation in protozoan parasites is considered a spontaneous process and antibodies to these variant antigens were cytotoxic. The clearance of the former antigen during antigenic switching is thought to occur by dilution of the original antigen. In this work, the authors provide in vitro and in vivo evidence, that low concentrations of antibodies against Variant-specific Surface Proteins (VSPs) of the intestinal parasite Giardia lamblia are not cytotoxic but induce a robust stimulation of the switching process and the release of the former antigen into extracellular microvesicles. This process is mediated by antibody-induced clustering of VSPs into Lo-phase membrane microdomains through the raftophilic capability of the highly conserved transmembrane domain of the VSPs.
- Albano H. Tenaglia
- , Lucas A. Luján
- & Hugo D. Luján
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Article
| Open AccessCryo-EM structures of Trypanosoma brucei gambiense ISG65 with human complement C3 and C3b and their roles in alternative pathway restriction
African Trypanosomes have developed elaborate immune evasion mechanisms. Here, the authors present the cryoelectron microscopy structures of a trypanosome surface receptor with human complement C3 and C3b, revealing several modes of complement interaction.
- Hagen Sülzen
- , Jakub Began
- & Sebastian Zoll
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Article
| Open AccessPlasmepsin X activates the PCRCR complex of Plasmodium falciparum by processing PfRh5 for erythrocyte invasion
Plasmodium falciparum is known to secrete an aspartic protease called plasmepsin X. Here, Triglia et al present a characterisation of plasmepsin X function in the context of erythrocyte invasion and its regulation of PCRCR, a complex that anchors the leading vaccine candidate PfRh5 to the parasite surface.
- Tony Triglia
- , Stephen W. Scally
- & Alan F. Cowman
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Article
| Open AccessStable endocytic structures navigate the complex pellicle of apicomplexan parasites
Apicomplexan parasites share complex cell pellicular structures that isolates the cytosol from most of the plasma membrane. Koreny et al show that, as an early adaptation to this barrier, dedicated stable endocytic structures occur at select sites in these cells. In Toxoplasma, plasma membrane homeostasis is particularly dependent on endocytosis.
- Ludek Koreny
- , Brandon N. Mercado-Saavedra
- & Ross F. Waller
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Article
| Open AccessSafe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening
Authors propose their splenic mimetic filtration method, microsphiltration, and utilise this approach in a drug-screen, to identify compounds that induce a stiffening effect on Plasmodium falciparum-infected erythrocytes. They proceed to assess safety and tolerability of one identified compound in a phase I clinical trial.
- Mario Carucci
- , Julien Duez
- & Pierre Buffet
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Article
| Open AccessPulmonary inflammation promoted by type-2 dendritic cells is a feature of human and murine schistosomiasis
Schistosomiasis, a parasitic helminth infection, causes pulmonary symptoms during acute and chronic infection. Here, Houlder et al characterise the pulmonary immune response and demonstrate the role type 2 dendritic cells play in lung inflammation.
- E. L. Houlder
- , A. H. Costain
- & A. S. MacDonald
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Article
| Open AccessThe Trypanosoma cruzi Antigen and Epitope Atlas: antibody specificities in Chagas disease patients across the Americas
This work reveals the diversity and extent of human antibody specificities in Chagas disease and provides a wealth of well-defined antigenic markers for diagnosis and development of serological applications for this neglected infectious disease.
- Alejandro D. Ricci
- , Leonel Bracco
- & Fernán Agüero
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Article
| Open AccessCryo-tomography reveals rigid-body motion and organization of apicomplexan invasion machinery
In this study, the authors use cryo-focused-ion-beammilling and cryo-electron tomography to image the apical complex of parasites in their native states. They report insights into the parasite invasion machinery in its protruded and retracted states in three dimensions, including all cytoskeletal assemblies, secretory organelles, and membranes intact.
- Long Gui
- , William J. O’Shaughnessy
- & Daniela Nicastro
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Article
| Open AccessThe RRM-mediated RNA binding activity in T. brucei RAP1 is essential for VSG monoallelic expression
Monoallelic VSG expression is essential for Trypanosoma brucei survival. Competition between TbRAP1’s RNA and dsDNA binding activities ensures that TbRAP1 sustains a high level expression of the active VSG while silencing other VSGs globally.
- Amit Kumar Gaurav
- , Marjia Afrin
- & Bibo Li
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Article
| Open AccessCryptosporidium uses CSpV1 to activate host type I interferon and attenuate antiparasitic defenses
Cryptosporidium parvum virus 1 is a virus harbored by the pathogenic protozoan Cryptosporidium parvum, and whose role in parasite biology and host interactions remains unclear. Here, Deng et al. demonstrate the impact this virus has on host response and infection outcome.
- Silu Deng
- , Wei He
- & Xian-Ming Chen
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Article
| Open AccessPotent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation
Drug resistance to current antimalarials is rising and new drugs and targets are urgently needed. Here the authors identify Plasmodium falciparum acyl-CoA synthetase 10 as a new target whose inhibition leads to a decrease in triacylglycerols.
- Selina Bopp
- , Charisse Flerida A. Pasaje
- & Dyann F. Wirth
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Article
| Open AccessThe Skp1-Cullin1-FBXO1 complex is a pleiotropic regulator required for the formation of gametes and motile forms in Plasmodium berghei
Raspha et al. apply proteomics and different microscopy approaches to investigate the role of ubiquitination in the lifecycle progression of Plasmodium berghei. They describe the location and function of proteins linked to the conserved SKP1/Culin1/FBXO1 complex (SCF) – a member of the cullinRING E3 ligases (CRLs).
- Ravish Rashpa
- , Natacha Klages
- & Mathieu Brochet
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Article
| Open AccessVariable microtubule architecture in the malaria parasite
Microtubules are a ubiquitous eukaryotic cytoskeletal element typically consisting of 13 protofilaments arranged in a hollow cylinder. Using CryoEM and subvolume averaging, Ferreira and Pražák et al. show that Plasmodium does not adhere to a single microtubule structure. Instead, the cytoskeleton changes substantially to produce a unique, fit for purpose structure and organisation at each stage of its life cycle.
- Josie L. Ferreira
- , Vojtěch Pražák
- & Kay Grünewald
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Article
| Open AccessGasdermin-D activation promotes NLRP3 activation and host resistance to Leishmania infection
Here, de Sá et al. show that Gasdermin-D is transiently activated in Leishmania-infected macrophages and promotes NLRP3 inflammasome activation, but not cell death. Gasdermin-D is cleaved into a noncanonical fragment, indicating that Leishmania subverts Gasdermin-D-mediated host response to establish leishmaniasis.
- Keyla S. G. de Sá
- , Luana A. Amaral
- & Dario S. Zamboni
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Article
| Open AccessThe Toxoplasma micropore mediates endocytosis for selective nutrient salvage from host cell compartments
Toxoplasma gondii acquires host cytosolic materials, yet the mechanism remains unknown. Wan et al. reveal the micropore as an essential organelle at the plasma membrane for endocytosis of host cytosolic proteins and biotin, and Golgi ceramide.
- Wenyan Wan
- , Hui Dong
- & Shaojun Long
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Article
| Open AccessRapid metabolic reprogramming mediated by the AMP-activated protein kinase during the lytic cycle of Toxoplasma gondii
Efficient metabolic regulation is key for parasite growth. Here, the authors report that Toxoplasma alters its AMPK phosphorylation during the lytic cycle, which reprograms parasite’s metabolism to ensure metabolic needs at different stages are met.
- Yaqiong Li
- , Zhipeng Niu
- & Bang Shen
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Article
| Open AccessProjected health impact of post-discharge malaria chemoprevention among children with severe malarial anaemia in Africa
Trial data have shown that post-discharge malaria chemoprevention (PDMC) reduces the risk of readmission and death in children previously hospitalised with severe malarial anaemia. Here, the authors use mathematical modelling to estimate the potential epidemiological impacts of PDMC in malaria-endemic countries in Africa.
- Lucy C. Okell
- , Titus K. Kwambai
- & Amani Thomas Mori
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Article
| Open AccessThe protein phosphatase 2A holoenzyme is a key regulator of starch metabolism and bradyzoite differentiation in Toxoplasma gondii
Protein phosphorylation and dephosphorylation are essential aspects of biology. Wang et al., report that Toxoplasma gondiiprotein phosphatase 2A (PP2A) mediated dephosphorylation is critical for starch metabolism and bradyzoite differentiation.
- Jin-Lei Wang
- , Ting-Ting Li
- & Xing-Quan Zhu
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Article
| Open AccessSlow growing behavior in African trypanosomes during adipose tissue colonization
Trypanosoma brucei parasites invade different organs, such as the central nervous system, adipose tissue, and skin in mammalian host. Here, Trindade et al. perform mathematical modelling to show that adipose tissue forms (ATFs) grow slower than the bloodstream forms and experimentally characterize the heterogeneous ATF populations and provide evidence that slow-growing forms are refractory to drug treatment.
- Sandra Trindade
- , Mariana De Niz
- & Luisa M. Figueiredo
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Article
| Open AccessApical anchorage and stabilization of subpellicular microtubules by apical polar ring ensures Plasmodium ookinete infection in mosquito
The structure of subpellicular microtubules (SPMTs) nucleated from the apical polar ring (APR) is essential for Plasmodium parasite morphogenesis, gliding motility, and invasion. Here, Qian et al. characterize the function of APR2 protein in P. yoelii ookinetes. Using co-localization analysis, proximity labeling, CoIP, expansion microscopy and FRAP, they show that APR2 binds to SMPTs and has a fixed position in APR. Deletion mutants fail to traverse the mosquito midgut as they fail to anchor SPMTs on APR, which affects invasive morphology and gliding motility.
- Pengge Qian
- , Xu Wang
- & Jing Yuan
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Article
| Open AccessHeme-deficient metabolism and impaired cellular differentiation as an evolutionary trade-off for human infectivity in Trypanosoma brucei gambiense
Decreased functionality and expression of trypanosome haptoglobin-hemoglobin receptor (HpHbR) is one of the evolutionary modifications that have allowed Trypanosoma brucei gambiense to infect humans. Here, Horakova et al. show that hemoglobin uptake in African trypanosomes is mediated almost exclusively by HpHbR and relevant for slender-to-stumpy differentiation. T. b. gambiense is poorly competent to differentiate into stumpy forms compared to T. b. brucei, due to reduced functionality of HpHbR.
- Eva Horáková
- , Laurence Lecordier
- & Julius Lukeš
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Article
| Open AccessImpact of pulmonary African trypanosomes on the immunology and function of the lung
A number of human African trypanosomiasis, or sleeping sickness, patients suffer from respiratory symptoms commonly attributed to cardiac insufficiency. Here, the authors characterise the role of pulmonary Trypanosoma brucei in respiratory infection.
- Dorien Mabille
- , Laura Dirkx
- & Guy Caljon
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Article
| Open AccessMechanochemical tuning of a kinesin motor essential for malaria parasite transmission
Plasmodium kinesin-8B is essential for male gamete formation and its absence blocks parasite transmission. Using cryo-EM and TIRF, the authors report how kinesin-8B motor domains are tuned to support microtubule motility and depolymerase activity.
- Tianyang Liu
- , Fiona Shilliday
- & Carolyn A. Moores
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Article
| Open AccessIL-33 induces thymic involution-associated naive T cell aging and impairs host control of severe infection
Immunosuppression as a result of severe infection impairs pathogen clearance and can increase susceptibility to secondary infection. Here, the authors dissect how T cell aging and the thymic involution that occurs during this process contribute to immunosuppression and find a key role for IL-33.
- Lei Xu
- , Chuan Wei
- & Xiaojun Chen
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Article
| Open AccessDecreased susceptibility of Plasmodium falciparum to both dihydroartemisinin and lumefantrine in northern Uganda
In this work, susceptibilities to two key antimalarials, dihydroartemisinin and lumefantrine, were associated with multiple genetic polymorphisms in Plasmodium falciparum, and were lower in northern Uganda, where resistance-mediating mutations have emerged, compared to eastern Uganda.
- Patrick K. Tumwebaze
- , Melissa D. Conrad
- & Philip J. Rosenthal
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Article
| Open AccessGenome-wide functional screening of drug-resistance genes in Plasmodium falciparum
Plasmodium falciparum malaria is treated using artemisinin combination therapy (ACT), in which artemisinin is supplied along with partner drugs such as mefloquine, piperaquine, and lumefantrine. However, resistance has been reported in endemic regions. To identifying new effector genes involved in resistance, Iwanaga et al. develop a large scale transgenic screen with genomic libraries of resistance strains. Using this approach they provide evidence that transcriptional upregulation of pfmdr7 contributes to mefloquine resistance in a clinical isolate.
- Shiroh Iwanaga
- , Rie Kubota
- & Chairat Uthaipibull
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Article
| Open AccessNeutralizing and interfering human antibodies define the structural and mechanistic basis for antigenic diversion
The Plasmodium falciparum Merozoite Surface Protein 1 (MSP-1) is a prime vaccine candidate for malaria. Here, the authors structurally and functionally characterise a panel of naturally acquired MSP-1 specific antibodies to identify one with potent broadly neutralising activity and better understand immune evasion mechanisms.
- Palak N. Patel
- , Thayne H. Dickey
- & Niraj H. Tolia
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Article
| Open AccessA unique Toxoplasma gondii haplotype accompanied the global expansion of cats
Toxoplasma gondii can infect all warm-blooded animals, with felidae being the definitive hosts. Despite this broad host range, most clinical and animal isolates belong to few clonal lineages. Here, Galal et al. perform whole-genome sequencing of isolates from distinct geographical regions and estimate T. gondii mutation rate and generation time. They find that recent waves of migration disseminated the parasite from Old to New World and identify a unique haplotype that likely accompanied the global expansion of cats and is today common to all intercontinental lineages and hybrid populations.
- Lokman Galal
- , Frédéric Ariey
- & Aurélien Mercier
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Article
| Open AccessSingle cell and spatial transcriptomic analyses reveal microglia-plasma cell crosstalk in the brain during Trypanosoma brucei infection
Detailed insight into how the brain responds to Trypanosoma brucei infection is lacking. Here, single cell and spatial transcriptomics are integrated to characterise this response, identifying a unique crosstalk between microglia and plasma cells.
- Juan F. Quintana
- , Praveena Chandrasegaran
- & Annette MacLeod
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Article
| Open AccessA G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin
In a recent clinical trial for oral administration of cipargamin in individuals with malaria, there was an emergence of recrudescent parasites with a G358S mutation in PfATP4. In this work, the authors investigate the effect of this mutation on the function of the ATPase, on parasite growth and susceptibility to antimalarial drugs.
- Deyun Qiu
- , Jinxin V. Pei
- & Adele M. Lehane
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Article
| Open AccessHigh-throughput small molecule screen identifies inhibitors of microsporidia invasion and proliferation in C. elegans
Microsporidia are fungal-related intracellular parasites that infect animals and humans. Here, Murareanu et al. develop a high-throughput screening method using the nematode C. elegans as a host, and identify several compounds that inhibit microsporidia infection through different mechanisms.
- Brandon M. Murareanu
- , Noelle V. Antao
- & Aaron W. Reinke
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Article
| Open AccessStructure of the malaria vaccine candidate Pfs48/45 and its recognition by transmission blocking antibodies
Pfs48/45, a surface protein of Plasmodium falciparum, is a promising anti-malarial vaccine candidate whose structure is not entirely resolved. Here, the authors present the structure of the full-length molecule, and characterise the binding and activity of transmission blocking antibodies.
- Kuang-Ting Ko
- , Frank Lennartz
- & Matthew K. Higgins
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Matters Arising
| Open AccessRelationship of circulating Plasmodium falciparum lifecycle stage to circulating parasitemia and total parasite biomass
- Michael F. Duffy
- , Gerry Q. Tonkin-Hill
- & Anthony T. Papenfuss
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Matters Arising
| Open AccessReply to: Relationship of circulating Plasmodium falciparum lifecycle stage to circulating parasitemia and total parasite biomass
- Richard Thomson-Luque
- , Lasse Votborg-Novél
- & Silvia Portugal
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Article
| Open AccessA multi-adenylate cyclase regulator at the flagellar tip controls African trypanosome transmission
Trypanosomes can sense signal molecules and coordinate their movement in response to such signals, a phenomenon termed social motility (SoMo). Here, Bachmaier et al show that cyclic AMP response protein 3 (CARP3) localization to the flagellar tip and its interaction with a number of different adenylate cyclases is essential for migration to tsetse fly salivary glands and for SoMo, therewith linking SoMo and cAMP signaling to trypanosome transmission.
- Sabine Bachmaier
- , Giacomo Giacomelli
- & Michael Boshart
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Article
| Open AccessGenome-scale RNA interference profiling of Trypanosoma brucei cell cycle progression defects
Progression of the canonical eukaryotic cell cycle is tightly regulated. While the cell cycle control of flagellated protozoa Trypanosoma brucei shares conserved features with other eukaryotes certain cell cycle checkpoints are absent. Here, Marques et al. provide a genome-scale RNAi screen followed by sorting of parasites according to their cell cycle stage to inform about cell cycle regulators of bloodstream T. brucei.
- Catarina A. Marques
- , Melanie Ridgway
- & David Horn
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Article
| Open AccessInvariant surface glycoprotein 65 of Trypanosoma brucei is a complement C3 receptor
Trypanosomes evade the immune response through antigenic variation of a surface coat containing variant surface glycoproteins (VSG). They also express invariant surface glycoproteins (ISGs), which are less well understood. Here, Macleod et al. show that ISG65 of T. brucei is a receptor for complement component 3. They provide the crystal structure of T. brucei ISG65 in complex with complement C3d and show evidence that ISG65 is involved in reducing trypanosome susceptibility to C3-mediated clearance in vivo.
- Olivia J. S. Macleod
- , Alexander D. Cook
- & Mark Carrington
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Article
| Open AccessRepurposing the mitotic machinery to drive cellular elongation and chromatin reorganisation in Plasmodium falciparum gametocytes
The sexual blood stages of Plasmodium falciparum develop through five morphologically distinct stages culminating in mature crescent-shaped gametocytes that can be transmitted from the mammalian host to the mosquito vector. Here, Li et al. apply different microscopy and tomography approaches to characterize how the microtubule organizing center and cytoplasmic and nuclear microtubules are organized and oriented during these different stages in the absence of genome replication and mitosis.
- Jiahong Li
- , Gerald J. Shami
- & Leann Tilley
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Article
| Open AccessProteomic characterization of the Toxoplasma gondii cytokinesis machinery portrays an expanded hierarchy of its assembly and function
The basal complex is orchestrating Toxoplasma gondii cell division steps. Here, the authors use proximity biotinylation to map the proteome of this contractile ring, identify components acting on its formation, stability and constriction, and reveal bidirectional daughter budding.
- Klemens Engelberg
- , Tyler Bechtel
- & Marc-Jan Gubbels
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Article
| Open AccessIFN-γ stimulated murine and human neurons mount anti-parasitic defenses against the intracellular parasite Toxoplasma gondii
Toxoplasma gondii can persist in neurons in the central nervous system, presumably because neurons have limited cell-intrinsic immune responses. However, here, Chandrasekaran et al. show that IFN-gamma stimulated primary murine neurons can clear T. gondii and that IFN-gamma stimulated murine and human neurons show decreased infection rates.
- Sambamurthy Chandrasekaran
- , Joshua A. Kochanowsky
- & Anita A. Koshy