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Article
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Differentiation granules, a dynamic regulator of T. brucei development
The African trypanosome Trypanosoma brucei has been shown to form stress granules in vitro that might be repurposed to enable differentiation and facilitate parasite transmission. Here, Cayla et al. show that differentiation between slender and stumpy forms does involve membrane-less granules that are different from nutritional stress granules.
- Mathieu Cayla
- , Christos Spanos
- & Keith R. Matthews
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Article
| Open Access
Toxoplasma gondii actin filaments are tuned for rapid disassembly and turnover
Actin is critical to the survival of the parasite Toxoplasma gondii. In this study, Hvorecny and Sladewski et al. show that T. gondii actin forms intrinsically dynamic filaments in vitro due to differences in assembly contacts in the D-loop.
- Kelli L. Hvorecny
- , Thomas E. Sladewski
- & Aoife T. Heaslip
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Article
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Revisiting the Plasmodium sporozoite inoculum and elucidating the efficiency with which malaria parasites progress through the mosquito
Using unique single mosquito data the authors revisit the core quantitative relationships between sequential stages of Plasmodium parasites in their vector host. Their findings demonstrate the importance of mosquito parasite burden in onward transmission success.
- Sachie Kanatani
- , Deborah Stiffler
- & Photini Sinnis
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Sustained rhoptry docking and discharge requires Toxoplasma gondii intraconoidal microtubule-associated proteins
The authors identified a series of cytoskeletal proteins involved in the discharge of invasion-related organelles in Toxoplasma gondii. They successfully delineated their functions through the utilization of expansion and cryo-electron microscopy.
- Nicolas Dos Santos Pacheco
- , Albert Tell i Puig
- & Dominique Soldati-Favre
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VESPA: an optimized protocol for accurate metabarcoding-based characterization of vertebrate eukaryotic endosymbiont and parasite assemblages
DNA sequencing methods for characterizing microbial communities are well developed for bacteria, archaea and fungi, but less so for eukaryotic parasites and commensals. Here, the authors present an optimized and validated metabarcoding protocol for host-associated eukaryotic communities.
- Leah A. Owens
- , Sagan Friant
- & Tony L. Goldberg
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Article
| Open Access
Atypical flagella assembly and haploid genome coiling during male gamete formation in Plasmodium
Gametogenesis is critical for sexual reproduction. Using volume electron microscopy, Hair et al report the structural organisation of the haploid nucleus coiled around the axoneme of the Plasmodium berghei male microgamete.
- Molly Hair
- , Flávia Moreira-Leite
- & Sue Vaughan
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Article
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3D reconstructions of parasite development and the intracellular niche of the microsporidian pathogen Encephalitozoon intestinalis
Microsporidia are obligate intracellular parasitic fungi that can cause opportunistic infections in humans. Here, Antao et al. investigate the intracellular life cycle of human-infecting Encephalitozoon intestinalis using serial block-face scanning electron microscopy to characterize parasite organelle development and host-cell mitochondrial remodeling.
- Noelle V. Antao
- , Cherry Lam
- & Gira Bhabha
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Article
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Extracellular vesicles could be a putative posttranscriptional regulatory mechanism that shapes intracellular RNA levels in Plasmodium falciparum
Here, Kioko et al. describe a putative posttranscriptional RNA regulation mechanism involving secreted extracellular vesicles to maintain the intracellular steady-state RNA levels during the asexual blood stage of malaria parasites.
- Mwikali Kioko
- , Alena Pance
- & Abdirahman I. Abdi
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Article
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Cryo-electron microscopy of IgM-VAR2CSA complex reveals IgM inhibits binding of Plasmodium falciparum to Chondroitin Sulfate A
Placental malaria parasite binds to host IgM however its functional importance was not understood. Here, authors resolved structure of IgM-VAR2CSA complex using cryo-EM to show that IgM masks VAR2CSA and inhibits its binding to receptor.
- Reetesh Raj Akhouri
- , Suchi Goel
- & Ulf Skoglund
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A transcriptional network required for bradyzoite development in Toxoplasma gondii is dispensable for recrudescent disease
Toxoplasma gondii can develop into dormant bradyzoites that persist in tissue and can be reactivated. Here the authors identify an RNA binding protein that they call Regulator of Cystogenesis 1 (ROCY1), and show that it is required for bradyzoite development in vitro and in vivo but is not required for long term persistence of parasites that reactivate in a mouse model of recrudescence.
- Sarah L. Sokol-Borrelli
- , Sarah M. Reilly
- & Jon P. Boyle
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Article
| Open Access
The structure of a Plasmodium vivax Tryptophan Rich Antigen domain suggests a lipid binding function for a pan-Plasmodium multi-gene family
Although the precise function of Tryptophan rich antigen multi-gene family (TRAgs) proteins is not known in any Plasmodium species several members of the P. vivax TRAg family have been reported to have red blood cell binding properties. Here, Kundu and Naskar et al. provide the X-ray crystallography structure of a P. vivax TRAg domain of PVP01_0000100. Structural and biochemical assays suggest a lipid binding function for a pan-Plasmodium multi-gene family.
- Prasun Kundu
- , Deboki Naskar
- & Julian C. Rayner
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Article
| Open Access
FAP106 is an interaction hub for assembling microtubule inner proteins at the cilium inner junction
Microtubule inner proteins (MIPs) contribute to species-specific motility characteristics but are largely unstudied. Here, the authors combine functional, structural and proteomic analysis in T. brucei to advance fundamental understanding of MIP assembly and identify trypanosome-specific MIPs required for motility.
- Michelle M. Shimogawa
- , Angeline S. Wijono
- & Kent L. Hill
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Origin and arrangement of actin filaments for gliding motility in apicomplexan parasites revealed by cryo-electron tomography
Apicomplexan parasites utilize a unique actomyosin system to mediate motility and host cell invasion. Here, the authors apply cryo-ET to Cryptosporidium parvum and Toxoplasma gondii to visualize the F-actin architecture in the native cellular context.
- Matthew Martinez
- , Shrawan Kumar Mageswaran
- & Yi-Wei Chang
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Article
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Development of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures
Suitable in vitro models allowing to assess Plasmodium liver stage development are still limited. Here, Yang et al. show that hepatocytes derived from human hepatocyte organoids (HepOrgs) can support P. falciparum development. This allowed for the identification and validation of the importance of the host factor, scavenger receptor B1 (SRB1), in parasite development.
- Annie S. P. Yang
- , Devanjali Dutta
- & Robert W. Sauerwein
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Article
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Sequential roles for red blood cell binding proteins enable phased commitment to invasion for malaria parasites
Malaria parasites invade erythrocytes to proliferate, but visualizing this rapid process is challenging. Here the authors use live imaging and genome-editing of P. knowlesi to dissect invasion and establish the roles of two vital parasite proteins.
- Melissa N. Hart
- , Franziska Mohring
- & Robert W. Moon
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Article
| Open Access
pH-dependence of the Plasmodium falciparum chloroquine resistance transporter is linked to the transport cycle
PfCRT is a chloroquine resistance transporter from malaria parasite Plasmodium falciparum, which is sensitive to acidic pH. Here, the authors show that residue E207 is critical for pH sensing by PfCRT, using alanine-scanning mutagenesis, MD simulations and drug uptake assays.
- Fiona Berger
- , Guillermo M. Gomez
- & Michael Lanzer
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Article
| Open Access
Distinct 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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A 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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The 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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Structural 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
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EB1 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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Translational 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
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Antibodies 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
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Plasmepsin 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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Stable 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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Safe 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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Cryo-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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Potent 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
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The 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
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Variable 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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| Open Access
The 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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Rapid 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
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Slow 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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Apical 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 Access
Impact 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 Access
Mechanochemical 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 Access
A 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 Access
High-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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Matters Arising
| Open Access
Relationship 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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Article
| Open Access
A 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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| Open Access
Repurposing 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 Access
Proteomic 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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| Open Access
Maturation and substrate processing topography of the Plasmodium falciparum invasion/egress protease plasmepsin X
Egress of Plasmodium from host erythrocytes is mediated by effector proteins. Aspartic protease plasmepsin X (PM X) regulates the activity for many of these effectors, is essential for replication and is a promising drug target. Here, Mukherjee et al. map the self-cleavage sites of PM X, show that the N-terminal part of its prodomain is required for intracellular trafficking and correlate the maturation and subcellular activity of PM X in microneme, exoneme and rhoptry organelle function.
- Sumit Mukherjee
- , Suong Nguyen
- & Daniel E. Goldberg
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Article
| Open Access
Tryptophan C-mannosylation is critical for Plasmodium falciparum transmission
Here, Lopaticki et al. show that Plasmodium falciparum expresses a Dpy19 C-mannosyltransferase in the endoplasmic reticulum that glycosylates TSR domains. Functional characterization shows that PfDpy19 plays a critical role in transmission through mosquitoes as PfDpy19-deficiency abolishes C-glycosylation and destabilizes proteins relevant for gametogenesis and oocyst formation.
- Sash Lopaticki
- , Robyn McConville
- & Justin A. Boddey
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Article
| Open Access
Humanized mice for investigating sustained Plasmodium vivax blood-stage infections and transmission
Plasmodium vivax is the most widespread human malaria parasite but due to its tropism for immature red blood cells in vitro culturing and studies are difficult. Here, LuizaBatista et al. generate a humanized mouse supporting human erythropoiesis and allowing asexual and sexual development of P. vivax in bone marrow and peripheral blood, as well as transmission to mosquitoes.
- Camilla Luiza-Batista
- , Sabine Thiberge
- & Sylvie Garcia
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Article
| Open Access
A time-resolved multi-omics atlas of Acanthamoeba castellanii encystment
Encystment is a process that allows free-living and parasitic amoebae to survive in unfavorable environments. Here, Bernard et al. provide detailed insights into the early stages of encystment of Acanthamoeba castellanii by integrating RNA-Seq, proteomics and phosphoproteomics data sets.
- Clément Bernard
- , Marie Locard-Paulet
- & Ascel Samba-Louaka
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Article
| Open Access
Bromodomain factor 5 is an essential regulator of transcription in Leishmania
Leishmania use large (5–10 kb) transcriptional start regions, where the chromatin is highly enriched for acetylated histones, to drive the expression of polycistronic gene arrays. Here the authors show bromodomain-containing protein BDF5 is enriched at transcriptional start sites and its depletion leads to cell death in vitro and in murine infections, and they identify its interactors.
- Nathaniel G. Jones
- , Vincent Geoghegan
- & Jeremy C. Mottram
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Article
| Open Access
Malaria parasite heme biosynthesis promotes and griseofulvin protects against cerebral malaria in mice
Malaria parasite heme pathway is non-essential for blood stages, but essential for mosquito and liver stages. Here, the authors show that heme pathway promotes cerebral pathogenesis by enhancing hemozoin formation and that targeting it with griseofulvin inhibits cerebral malaria in mice.
- Manjunatha Chandana
- , Aditya Anand
- & Viswanathan Arun Nagaraj
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Article
| Open Access
Extracellular release of two peptidases dominates generation of the trypanosome quorum-sensing signal
Trypanosomes use quorum-sensing (QS) signalled by oligopeptides to generate transmission-competent stumpy forms. Here, Tettey et al. perform mass spectrometry analysis to identify secreted peptidases and systematically assess each of the identified candidates for their role in stumpy formation in vivo. Two enzymes, oligopeptidase B and metallocarboxypeptidase 1 are shown to dominate QS.
- Mabel Deladem Tettey
- , Federico Rojas
- & Keith R. Matthews
Metabolic plasticity, essentiality and therapeutic potential of ribose-5-phosphate synthesis in Toxoplasma gondii