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| Open Accessγδ T cells control murine skin inflammation and subcutaneous adipose wasting during chronic Trypanosoma brucei infection
Trypansome brucei infection can result in colonisation of the skin but how this impacts the skin architecture and immune response has not been fully resolved. Here the authors apply a spatially resolved single cell transcriptomics approach in a murine model of infection, and suggest a role for IL-17- producing γδ T cells in the immune response to T. brucei skin infection.
- Juan F. Quintana
- , Matthew C. Sinton
- & Annette MacLeod
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Article
| Open AccessFAP106 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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Article
| Open AccessBehavioural individuality determines infection risk in clonal ant colonies
Behaviour drives infection risk in social groups. Here, Li et al. show that depending on the behavioural role of clonal ants in a colony, genetically identical individuals face vastly different risks of becoming infected with parasitic nematodes.
- Zimai Li
- , Bhoomika Bhat
- & Yuko Ulrich
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Article
| Open AccessPropensity of selecting mutant parasites for the antimalarial drug cabamiquine
Authors utilize a number of models (mathematical, in vitro and in vivo infection) to analyse pre-clinical and Phase I clinical trial data, in regard to potential risk of resistance associated with a Plasmodium falciparum inhibitor, cabamiquine.
- Eva Stadler
- , Mohamed Maiga
- & Thomas Spangenberg
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Article
| Open AccessOuter membrane vesicles from a mosquito commensal mediate targeted killing of Plasmodium parasites via the phosphatidylcholine scavenging pathway
Here, Gao and colleagues show that the mosquito symbiotic bacterium Serratia ureilytica produces vesicles that deliver an anti-Plasmodium effector to the Plasmodium parasite and render mosquitoes resistant to the infection of malaria parasites.
- Han Gao
- , Yongmao Jiang
- & Sibao Wang
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Article
| Open AccessNovel insights into the role of long non-coding RNA in the human malaria parasite, Plasmodium falciparum
In eukaryotes, long non-coding RNAs (lncRNAs) are regulators of gene expression. Here the authors identify lncRNAs implicated in pathogenicity and sexual differentiation of the human malaria parasite, P. falciparum, opening novel avenues towards therapeutic strategies.
- Gayani Batugedara
- , Xueqing M. Lu
- & Karine G. Le Roch
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Article
| Open AccessOrigin 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
| Open AccessDevelopment 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
| Open AccessSequential 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 AccessAffinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection
Here, the authors use cryo-EM to solve the structures of seven potent human antibodies, and demonstrate in vivo protection in a liver burden assay, using chimeric Plasmodium berghei sporozoites expressing Plasmodium falciparum circumsporozoite protein.
- Gregory M. Martin
- , Jonathan L. Torres
- & Andrew B. Ward
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Article
| Open AccessMapping diversity in African trypanosomes using high resolution spatial proteomics
The molecular diversity between parasite species and life-stages correlate with diversity in the hosts they infect or the pathologies they cause. Here, Moloney et al., map the spatial proteomes of two African trypanosome species across two life stages and identify key routes of parasitic adaptation.
- Nicola M. Moloney
- , Konstantin Barylyuk
- & Paula MacGregor
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Article
| Open AccesspH-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 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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| 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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| 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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| 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