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| Open AccessMalaria parasite DNA-harbouring vesicles activate cytosolic immune sensors
STING is an intracellular DNA sensor that can alter response to infection, but in the case of malaria it is unclear how parasite DNA in red blood cells (RBCs) reaches DNA sensors in immune cells. Here the authors show that STING in human monocytes can sense P. falciparum nucleic acids transported from infected RBCs via parasite extracellular vesicles.
- Xavier Sisquella
- , Yifat Ofir-Birin
- & Neta Regev-Rudzki
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Article
| Open AccessThe anthelmintic praziquantel is a human serotoninergic G-protein-coupled receptor ligand
Schistosomiasis is caused by infection with the flatworm Schistosoma, and praziquantel is the drug of choice for its treatment. Here, Chan and colleagues identify praziquantel as a ligand for the human serotoninergic 5-HT2B G-protein-coupled receptor, and reveal a function for praziquantel as a regulator of vascular tone in treated hosts.
- John D. Chan
- , Pauline M. Cupit
- & Jonathan S. Marchant
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| Open AccessWild bonobos host geographically restricted malaria parasites including a putative new Laverania species
Unlike chimpanzees and gorillas, bonobos have not been found infected by malaria parasites in the wild. Here, Liu et al. report more thorough survey and sequencing results showing that bonobos host malaria parasites, including a yet-unknown species, but only in the eastern-most part of their range.
- Weimin Liu
- , Scott Sherrill-Mix
- & Beatrice H. Hahn
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| Open AccessAtomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin
Leishmaniasis is a parasitic disease transmitted by the bite of infected sand flies. Here the authors describe an atomic resolution cryo-EM structure of the Leishmania ribosome in complex with the recently approved drug paromomycin (PAR) and highlight conserved elements in the drug binding pocket that mediate PAR deleterious effects on the parasite.
- Moran Shalev-Benami
- , Yan Zhang
- & Georgios Skiniotis
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Article
| Open AccessHuman Cyclophilin B forms part of a multi-protein complex during erythrocyte invasion by Plasmodium falciparum
Invasion of red blood cells by Plasmodium falciparum is a complex process and relies on several receptor-ligand interactions. Here, the authors show that human cyclophilin B binds Plasmodium surface protein PfRhopH3 and that interruption of this interaction reduces invasion by 80%.
- Prem Prakash
- , Mohammad Zeeshan
- & Pawan Malhotra
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Article
| Open AccessAssessing the impact of imperfect adherence to artemether-lumefantrine on malaria treatment outcomes using within-host modelling
Artemether lumefantrine is widely used for the treatment of uncomplicated malaria. The impact of imperfect patient adherence to the six-dose regimen is hard to assess. Using adherence data for unsupervised patients, the authors model how suboptimal adherence affects treatment outcomes.
- Joseph D. Challenger
- , Katia Bruxvoort
- & Lucy C. Okell
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| Open AccessPlasmodium DNA-mediated TLR9 activation of T-bet+ B cells contributes to autoimmune anaemia during malaria
Autoimmune anaemia often accompanies Plasmodium infection and malaria, but how anaemia is induced is still unclear. Here the authors show that Plasmodium DNA, together with interferon-γ, can activate B cells to induce auto-antibodies that recognize red blood cells and promote their removal to contribute to anaemia onset.
- J. Rivera-Correa
- , J. J. Guthmiller
- & A. Rodriguez
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Article
| Open AccessIdentifying host regulators and inhibitors of liver stage malaria infection using kinase activity profiles
Host kinases facilitate Plasmodium liver stage (LS) infection, but systematic accounting of important players is lacking. Here, the authors use a computational approach and kinase activity profiles to identify host kinase regulators of LS infection and drugs that could eliminate parasite burden.
- Nadia Arang
- , Heather S. Kain
- & Alexis Kaushansky
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| Open AccessExamining the human infectious reservoir for Plasmodium falciparum malaria in areas of differing transmission intensity
Heterogeneity in the transmission potential of individual hosts is an important feature of malaria. Here, the authors perform a multi-regional study of the human infectious reservoir in malaria-endemic regions of Burkina Faso and Kenya.
- Bronner P. Gonçalves
- , Melissa C. Kapulu
- & Teun Bousema
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Article
| Open AccessVariant surface glycoprotein density defines an immune evasion threshold for African trypanosomes undergoing antigenic variation
Trypanosoma brucei evades the host immune system through replacement of a variant surface glycoprotein (VSG) coat. Here, the authors show that VSG replacement takes several days to complete, and the parasite is vulnerable to the host immune system for a short period of time during the process.
- Jason Pinger
- , Shanin Chowdhury
- & F. Nina Papavasiliou
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Article
| Open AccessProtein O-fucosylation in Plasmodium falciparum ensures efficient infection of mosquito and vertebrate hosts
The role of O-glycosylation in the malaria life cycle is largely unknown. Here, the authors identify a Plasmodium protein O-fucosyltransferase and show that it is important for normal trafficking of a subset of surface proteins, particularly CSP and TRAP, and efficient infection of mosquito and vertebrate hosts.
- Sash Lopaticki
- , Annie S. P. Yang
- & Justin A. Boddey
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Article
| Open AccessA Plasmodium yoelii HECT-like E3 ubiquitin ligase regulates parasite growth and virulence
Many strains of Plasmodium differ in virulence, but factors that control these distinctions are not known. Here the authors comparatively map virulence loci using the offspring from a P. yoelii YM and N67 genetic cross, and identify a putative HECT E3 ubiquitin ligase that may explain the variance.
- Sethu C. Nair
- , Ruixue Xu
- & Xin-zhuan Su
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Article
| Open AccessEarly-life disruption of amphibian microbiota decreases later-life resistance to parasites
Early-life microbiota alterations can affect infection susceptibility later in life, in animal models. Here, Knutie et al. show that manipulating the microbiota of tadpoles leads to increased susceptibility to parasitic infection in adult frogs, in the absence of substantial changes in the adults’ microbiota.
- Sarah A. Knutie
- , Christina L. Wilkinson
- & Jason R. Rohr
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| Open AccessAGC family kinase 1 participates in trogocytosis but not in phagocytosis in Entamoeba histolytica
Entamoeba histolytica can kill host cells by trogocytosis, while it ingests dead cells by phagocytosis. Here, Somlata et al. show that EhAGCK1, an AGC family kinase, is specifically involved in trogocytosis, shedding light on the molecular differences between trogocytosis and phagocytosis.
- Somlata
- , Kumiko Nakada-Tsukui
- & Tomoyoshi Nozaki
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Article
| Open AccessAn exported protein-interacting complex involved in the trafficking of virulence determinants in Plasmodium-infected erythrocytes
Plasmodium-infected red blood cells export virulence factors, such asPfEMP1, to the cell surface. Here, the authors identify a protein complex termed EPIC that interacts with PfEMP1 during export, and they show that knockdown of an EPIC component affects parasite virulence.
- Steven Batinovic
- , Emma McHugh
- & Leann Tilley
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Article
| Open AccessSkin parasite landscape determines host infectiousness in visceral leishmaniasis
Parasitemia has been considered the main determinant of visceral leishmaniasis transmission. By combining imaging, qPCR and experimental xenodiagnoses with mathematical models, Doehl et al. argue that the patchy landscape of parasites in the skin is necessary to explain infectiousness.
- Johannes S. P. Doehl
- , Zoe Bright
- & Paul M. Kaye
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| Open AccessPfCDPK1 mediated signaling in erythrocytic stages of Plasmodium falciparum
Calcium dependent protein kinase 1 (CDPK1) plays an important role in asexual development of Plasmodium falciparum. Using phosphoproteomics and conditional knockdown of CDPK1, the authors here identify CDPK1 substrates and a cross-talk between CDPK1 and PKA, and show the role of CDPK1 in parasite invasion.
- Sudhir Kumar
- , Manish Kumar
- & Pushkar Sharma
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| Open AccessMyosin-dependent cell-cell communication controls synchronicity of division in acute and chronic stages of Toxoplasma gondii
The mechanism by whichToxoplasma gondiiachieves synchronized cell division is incompletely understood. Here, the authors identify an intravacuolar cell-cell communication that ensures synchronized division and depends on myosin I.
- Karine Frénal
- , Damien Jacot
- & Dominique Soldati-Favre
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| Open AccessHundreds of dual-stage antimalarial molecules discovered by a functional gametocyte screen
There is a need forPlasmodium transmission blocking drugs for malaria elimination. Here, Miguel-Blanco et al. screen >10,000 compounds against stage V female gametocytes, identify active compounds belonging to 57 chemotypes and confirm transmission blocking activity of four selected compounds in vitro.
- Celia Miguel-Blanco
- , Irene Molina
- & Esperanza Herreros
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Article
| Open AccessDynamic transcriptomes identify biogenic amines and insect-like hormonal regulation for mediating reproduction in Schistosoma japonicum
For reproduction, the human parasiteSchistosoma japonicumrelies on a complex and incompletely understood interplay between female and male schistosomes. Here the authors sequence the transcriptome of female and male schistosomes across eight time points during sexual development.
- Jipeng Wang
- , Ying Yu
- & Wei Hu
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Article
| Open AccessA potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue
Benzoxaboroles have been shown to be active against different pathogens. Here, the authors show that the benzoxaborole AN3661 inhibitsPlasmodium falciparum in vitroand in mouse models, and identify a homologue of a mammalian cleavage and polyadenylation specificity factor as a drug target.
- Ebere Sonoiki
- , Caroline L. Ng
- & Philip J. Rosenthal
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Article
| Open AccessCationic amino acid transporters play key roles in the survival and transmission of apicomplexan parasites
Apicomplexans are parasites that use membrane transporters to scavenge essential nutrients from the host. Here the authors identify and characterize two apicomplexans transporters showing that these are crucial for cationic amino acid uptake, parasite survival and virulence.
- Esther Rajendran
- , Sanduni V. Hapuarachchi
- & Giel G. van Dooren
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| Open AccessP113 is a merozoite surface protein that binds the N terminus of Plasmodium falciparum RH5
The secretedPlasmodium falciparum protein RH5 is essential for invasion of erythrocytes and is a promising vaccine candidate. Here, Galaway et al. show that the N-terminal region of RH5 binds the GPI-anchored merozoite surface protein P113 and can elicit invasion-blocking antibodies.
- Francis Galaway
- , Laura G. Drought
- & Gavin J. Wright
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Article
| Open AccessIdentification of microsporidia host-exposed proteins reveals a repertoire of rapidly evolving proteins
Unbiased identification of proteins from pathogens that are exposed to a host can provide insight into host–pathogen interaction. Here, the authors use an enzymatic tagging method and mass spectrometry to identify rapidly evolvingNematocida microsporidia proteins when infecting C. elegans.
- Aaron W. Reinke
- , Keir M. Balla
- & Emily R. Troemel
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| Open AccessRelease of Plasmodium sporozoites requires proteins with histone-fold dimerization domains
Oocyst rupture and release of malaria sporozoites is needed for transmission of parasites from vector to humans. Here the authors identify two proteins, which they name ORP1 and ORP2, that form heterodimers and are required for oocyst rupture.
- Chiara Currà
- , Renate Gessmann
- & Inga Siden-Kiamos
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| Open AccessCyst-Wall-Protein-1 is fundamental for Golgi-like organelle neogenesis and cyst-wall biosynthesis in Giardia lamblia
Giardia lamblia is a human protozoan parasite with two diploid nuclei, which makes complete knock-out of a gene of interest challenging. Here the authors use a Cre/loxP-based approach to knock-out cyst-wall protein 1 (cwp1) and show that CWP1 is essential for cyst-wall biosynthesis.
- Jacqueline A. Ebneter
- , Sally D. Heusser
- & Carmen Faso
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Article
| Open AccessOxidative insult can induce malaria-protective trait of sickle and fetal erythrocytes
Carriers of haemoglobinopathies are protected from severe malaria, likely due to reduced surface expression of virulence factors. Here, Cyrklaff et al. show that, similar to haemoglobinopathies, a transient oxidative insult affects actin reorganization and mitigates the development of cerebral malaria in mice.
- Marek Cyrklaff
- , Sirikamol Srismith
- & Michael Lanzer
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Article
| Open AccessSplenic differentiation and emergence of CCR5+CXCL9+CXCL10+ monocyte-derived dendritic cells in the brain during cerebral malaria
Cerebral malaria is an often fatal complication ofPlasmodium infection involving accumulation of inflammatory leukocytes in the central nervous system. Here the authors map the development and trafficking of CCR5+ monocyte-derived dendritic cells from the spleen to the brains of Plasmodium bergheiANKA infected mice.
- Isabella C. Hirako
- , Marco A. Ataide
- & Ricardo T. Gazzinelli
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Article
| Open AccessStructures and stabilization of kinetoplastid-specific split rRNAs revealed by comparing leishmanial and human ribosomes
Leishmania donovani is a protozoan parasite that can cause fatal infections in humans. Here the authors present a high resolution cryoEM structure of the L. donovani80S ribosome and compare it to its human counterpart to provide insight into the basis for drug selectivity towards this eukaryotic parasite.
- Xing Zhang
- , Mason Lai
- & Z. Hong Zhou
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Article
| Open AccessInfected erythrocyte-derived extracellular vesicles alter vascular function via regulatory Ago2-miRNA complexes in malaria
Inflammatory response to malaria pathogen Plasmodium falciparumcan be triggered by infected red blood cell-derived extracellular vesicles (EVs). This study shows these EVs contain functional microRNA-Argonaute 2 complex that modulates gene expression and alter vascular barrier properties.
- Pierre-Yves Mantel
- , Daisy Hjelmqvist
- & Matthias Marti
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Article
| Open AccessThe structural basis for CD36 binding by the malaria parasite
Targeting of the CD36 scavenger receptor by the malaria parasite effector PfEMP1 prevents splenic clearance of infected erythrocytes. Here, the authors propose that diverse PfEMP1 achieve this by binding to a conserved phenylalanine residue in CD36 that is also required for lipoprotein binding.
- Fu-Lien Hsieh
- , Louise Turner
- & Matthew K. Higgins
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| Open AccessN-glycosylation enables high lateral mobility of GPI-anchored proteins at a molecular crowding threshold
How molecular crowding affects membrane protein diffusion and function is not known. Here the authors measure diffusion of variant surface glycoprotein on trypanosomes and discover a molecular crowding threshold that limits diffusion, and find that N-linked glycans help to prevent retarding intermolecular interactions.
- Andreas J. W. Hartel
- , Marius Glogger
- & Markus Engstler
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| Open AccessA broad analysis of resistance development in the malaria parasite
It is unclear whether new antimalarial compounds may rapidly lose effectiveness in the field because of parasite resistance. Here, Corey et al.investigate the acquisition of drug resistance and the extent to which common resistance mechanisms decrease susceptibility to a diverse set of 50 antimalarial compounds.
- Victoria C. Corey
- , Amanda K. Lukens
- & Elizabeth A. Winzeler
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| Open AccessThe machinery underlying malaria parasite virulence is conserved between rodent and human malaria parasites
Proteins SBP1 and MAHRP1 of the human malaria parasite are required for sequestration of infected red blood cells in major organs. Here, De Niz et al. identify homologous proteins in the rodent parasite Plasmodium berghei, showing that they play similar roles and supporting the usefulness of malaria mouse models.
- Mariana De Niz
- , Ann-Katrin Ullrich
- & Tobias Spielmann
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| Open AccessGlobally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies
Antimalarial chemotherapy relies on combination therapies (ACTs) consisting of an artemisinin derivative and a partner drug. Here, the authors study the effects of globally prevalent mutations in a multidrug resistance transporter (PfMDR1) on the parasite’s susceptibility to ACT drugs.
- M. Isabel Veiga
- , Satish K. Dhingra
- & David A. Fidock
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Article
| Open AccessAn essential malaria protein defines the architecture of blood-stage and transmission-stage parasites
Blood-stage malaria parasites replicate through a specialised type of cell division known as schizogony. Here, Absalon et al. identify a parasite protein that is essential during schizogony for cytokinesis and formation of the inner membrane complex, the structural scaffold of daughter parasites.
- Sabrina Absalon
- , Jonathan A. Robbins
- & Jeffrey D. Dvorin
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Article
| Open AccessUnconventional endosome-like compartment and retromer complex in Toxoplasma gondii govern parasite integrity and host infection
The retromer complex is a multi-protein component of the endosomal protein sorting machinery. Here, Sangaré et al. identify unique features in the retromer complex of the parasite Toxoplasma gondii, and show that it is crucial for the biogenesis of secretory organelles in this pathogen.
- Lamba Omar Sangaré
- , Tchilabalo Dilezitoko Alayi
- & Stanislas Tomavo
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Article
| Open AccessAncient human sialic acid variant restricts an emerging zoonotic malaria parasite
Plasmodium knowlesi infects macaques and can cause malaria in humans. Here, Dankwa et al. show that the absence of a sialic-acid component on the surface of macaque red blood cells (RBCs) limits infection of human RBCs with P. knowlesi, but the parasite can adapt to invade human RBCs by using alternative pathways.
- Selasi Dankwa
- , Caeul Lim
- & Manoj T. Duraisingh
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Article
| Open AccessGenomes of cryptic chimpanzee Plasmodium species reveal key evolutionary events leading to human malaria
African apes harbour six Plasmodium species, one of which gave rise to the human malaria parasite. Here, Sundaraman et al. use selective whole-genome amplification to determine genome sequences from two chimpanzee Plasmodiumspecies, shedding light on the evolutionary origin of the human parasite.
- Sesh A. Sundararaman
- , Lindsey J. Plenderleith
- & Beatrice H. Hahn
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Article
| Open AccessSynthetic RNA–protein modules integrated with native translation mechanisms to control gene expression in malaria parasites
Current strategies for regulatory control of gene expression are orthogonal to the host organism mechanisms. Here the authors demonstrate an RNA aptamer controlled system integrated into native regulatory pathways in the parasite Plasmodium falciparum.
- Suresh M. Ganesan
- , Alejandra Falla
- & Jacquin C. Niles
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Article
| Open AccessExport of malaria proteins requires co-translational processing of the PEXEL motif independent of phosphatidylinositol-3-phosphate binding
Export of Plasmodium falciparum proteins into infected erythrocytes relies upon the PEXEL motif in target proteins. Here Boddey et al.challenge the hypothesis that the PEXEL motif mediates export by binding PI(3)P and instead suggest it acts via cleavage by plasmepsin V.
- Justin A. Boddey
- , Matthew T. O’Neill
- & Alan F. Cowman
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Article
| Open AccessPhylogenomic and biogeographic reconstruction of the Trichinella complex
Trichinellosis is a globally important food-borne disease caused by roundworms of the Trichinella complex. Here the authors present genomic sequences representing all 12 recognized Trichinellaspecies and genotypes, and reconstruct their phylogeny and biogeography.
- Pasi K. Korhonen
- , Edoardo Pozio
- & Robin B. Gasser
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Article
| Open AccessFunctional profiles of orphan membrane transporters in the life cycle of the malaria parasite
The functions of many putative membrane transport proteins of malaria parasites are unknown. Here, Kenthirapalan et al. use mutant strains carrying targeted gene deletions to study the functions of 35 such proteins during the life cycle of Plasmodium bergheiin mosquito and mouse hosts.
- Sanketha Kenthirapalan
- , Andrew P. Waters
- & Taco W. A. Kooij
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Article
| Open AccessA vacuolar iron-transporter homologue acts as a detoxifier in Plasmodium
Iron is an essential nutrient but, in high concentrations, it is also toxic to cells. Here, Slavic et al. identify an iron transporter in malaria parasites that plays a major role in iron detoxification and is required for the parasite’s normal development.
- Ksenija Slavic
- , Sanjeev Krishna
- & Maria M. Mota
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Article
| Open AccessLocal admixture of amplified and diversified secreted pathogenesis determinants shapes mosaic Toxoplasma gondii genomes
Toxoplasma gondii is a parasite that causes zoonotic infections in humans. Here, the authors identify tandem amplification and diversification of secretory pathogenesis determinants in the T. gondiigenome and show that clade-specific inheritance of conserved haploblocks enriched for these determinants shapes population structure.
- Hernan Lorenzi
- , Asis Khan
- & L. David Sibley
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Article
| Open AccessHaem-activated promiscuous targeting of artemisinin in Plasmodium falciparum
The mechanism of action of artemisinin, an antimalarial drug, is not well understood. Here, the authors use a labelled artemisinin analogue to show that the drug is mainly activated by haem and then binds covalently to over 120 proteins in the malaria parasite, affecting many of its cellular processes.
- Jigang Wang
- , Chong-Jing Zhang
- & Qingsong Lin
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Article
| Open AccessAsparagine requirement in Plasmodium berghei as a target to prevent malaria transmission and liver infections
Malaria parasites obtain amino acids primarily from the host, but possess a gene encoding a putative asparagine synthetase. Here, the authors show that this enzyme is functional and that asparagine is crucial for the development of the parasite’s sexual stages in mosquitoes and liver stages in mice.
- Viswanathan A. Nagaraj
- , Dhanunjay Mukhi
- & Govindarajan Padmanaban
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Article
| Open AccessArtemisinin-resistant Plasmodium falciparum clinical isolates can infect diverse mosquito vectors of Southeast Asia and Africa
It is unknown whether artemisinin-resistant malaria parasites from Southeast Asia can infect any African species of Anopheles mosquitoes and thus spread to Africa. Here, St. Laurent et al. show that artemisinin-resistant isolates from Cambodia can indeed infect the major African vector, Anopheles coluzzii.
- Brandyce St. Laurent
- , Becky Miller
- & Rick M. Fairhurst
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Article
| Open AccessApe parasite origins of human malaria virulence genes
Antigens encoded by var genes are major virulence factors of the human malaria parasite Plasmodium falciparum. Here, Larremore et al. identify var-like genes in distantly related Plasmodiumspecies infecting African apes, indicating that these genes already existed in an ancestral ape parasite many millions of years ago.
- Daniel B. Larremore
- , Sesh A. Sundararaman
- & Caroline O. Buckee