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| Open AccessPreclinical characterization and target validation of the antimalarial pantothenamide MMV693183
Here, de Vries et al. perform a pre-clinical characterization of the antimalarial compound MMV693183: the compound targets acetyl-CoA synthetase, has efficacy in humanized mice against Plasmodium falciparum infection, blocks transmission to mosquito vectors, is safe in rats, and pharmacokinetic-pharmacodynamic modeling informs about a potential oral human dosing regimen.
- Laura E. de Vries
- , Patrick A. M. Jansen
- & Koen J. Dechering
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| Open AccessZoonotic origin of the human malaria parasite Plasmodium malariae from African apes
Plasmodium malariae is a cause of malaria in humans and related species have been identified in non-human primates. Here, the authors use genomic analyses to establish that human P. malariae arose from a host switch of an ape parasite whilst a species infecting New World monkeys can be traced to a reverse zoonosis.
- Lindsey J. Plenderleith
- , Weimin Liu
- & Paul M. Sharp
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| Open AccessRandomized clinical trial to assess the protective efficacy of a Plasmodium vivax CS synthetic vaccine
In this phase 2 clinical trial, the authors assess protective efficacy of a Plasmodium vivax circumsporozoite vaccine in naïve and semi-immune individuals from controlled human malaria infection as well as antibody and IFN-γ response to vaccination.
- Myriam Arévalo-Herrera
- , Xiomara Gaitán
- & Sócrates Herrera
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| Open AccessHeterotypic interactions drive antibody synergy against a malaria vaccine candidate
Antibodies can have synergistic effects, but mechanisms are not well understood. Here, Ragotte et al. identify three antibodies that bind neighbouring epitopes on CyRPA, a malaria vaccine candidate, and show that lateral interactions between the antibodies slow dissociation and inhibit parasite growth synergistically.
- Robert J. Ragotte
- , David Pulido
- & Simon J. Draper
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| Open AccessMark-release-recapture experiment in Burkina Faso demonstrates reduced fitness and dispersal of genetically-modified sterile malaria mosquitoes
Release of genetically-modified sterile mosquitoes is a potential method of malaria control but has yet to be tested in the field. Here, the authors perform a mark-release-recapture experiment and show that genetically-modified mosquitoes have reduced survival and dispersal compared to wild-types.
- Franck Adama Yao
- , Abdoul-Azize Millogo
- & Abdoulaye Diabaté
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| Open AccessDistinct kinetics of antibodies to 111 Plasmodium falciparum proteins identifies markers of recent malaria exposure
Serological markers of recent Plasmodium falciparum infection could be useful to estimate incidence. Here, the authors identify a combination of five serological markers to detect exposure to infection within the previous three months with >80% sensitivity and specificity.
- Victor Yman
- , James Tuju
- & Anna Färnert
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Article
| Open AccessIdentifying an optimal dihydroartemisinin-piperaquine dosing regimen for malaria prevention in young Ugandan children
Intermittent preventive treatment with dihydroartemisinin-piperaquine (DP) is protective in children against malaria. Here, the authors analyze plasma drug concentration, malaria incidence, and drug resistance markers from a clinical trial in Uganda and determine the optimal DP dosing regimen.
- Erika Wallender
- , Ali Mohamed Ali
- & Rada M. Savic
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| Open AccessAfucosylated Plasmodium falciparum-specific IgG is induced by infection but not by subunit vaccination
Here, Larsen et al. describe differences in Fc fucosylation of P. falciparum PfEMP1-specific IgG produced in response to natural infection versus VAR2CSA-type subunit vaccination, which leads to differences in the ability to induce FcγRIIIa-dependent natural killer cell degranulation.
- Mads Delbo Larsen
- , Mary Lopez-Perez
- & Gestur Vidarsson
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Article
| Open AccessMalaria parasites both repress host CXCL10 and use it as a cue for growth acceleration
The chemokine CXCL10 is associated with pathogenesis of cerebral malaria in Plasmodium falciparum infection. Here the authors show that P. falciparum produces extracellular vesicles laden with RNAs that are taken up by monocytes resulting in a RIG-I and HUR-1 mediated mechanism of inhibition of CXCL10 protein translation.
- Yifat Ofir-Birin
- , Hila Ben Ami Pilo
- & Neta Regev-Rudzki
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| Open AccessPlasmodium falciparum transcription in different clinical presentations of malaria associates with circulation time of infected erythrocytes
To understand malaria symptoms, several studies investigate association between parasite’s transcriptome and disease severity. Here, Thomson-Luque et al. reanalyze available transcriptomic data of P. falciparum and find that longer circulation of infected erythrocytes without sequestering to endothelial cells associates with decreasing parasitaemia and less severe disease.
- Richard Thomson-Luque
- , Lasse Votborg-Novél
- & Silvia Portugal
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| Open AccessThe apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite
Repeating fever is a hallmark of malaria. Here, a large-scale forward genetic screen in malaria-causing Plasmodium falciparum identifies genes associated with parasite tolerance to host fever, including apicoplast targeted isoprenoid biosynthesis—sharing features with artemisinin resistance.
- Min Zhang
- , Chengqi Wang
- & John H. Adams
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Article
| Open AccessStructural basis of LAIR1 targeting by polymorphic Plasmodium RIFINs
RIFINs are Plasmodium surface antigens that suppress the immune response by binding inhibitory receptors such as LAIR1. Here, Xu et al. characterize the interaction between RIFIN-variable 2 domain and a LAIR1 domain and identify LAIR1-binding RIFINs in several Plasmodium species.
- Kai Xu
- , Yiran Wang
- & Peter D. Kwong
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Article
| Open AccessThe epidemiology of Plasmodium vivax among adults in the Democratic Republic of the Congo
Plasmodium vivax generally accounts for a low proportion of malaria cases in Africa, but population-level data on the distribution of infections is limited. Here, the authors use data from the Democratic Republic of the Congo and show that the prevalence is low (~3%) and diffusely spread.
- Nicholas F. Brazeau
- , Cedar L. Mitchell
- & Jonathan J. Juliano
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Article
| Open AccessImpact of an accelerated melting of Greenland on malaria distribution over Africa
Release of freshwater into the oceans as a result of ice sheet melting could impact the distribution of climate-sensitive diseases. Here, the authors show that a rapid ice sheet melting in Greenland could cause an emergence of malaria in Southern Africa whilst transmission risks in West Africa may decline.
- Alizée Chemison
- , Gilles Ramstein
- & Cyril Caminade
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| Open AccessComposition and stage dynamics of mitochondrial complexes in Plasmodium falciparum
Applying complexome profiling, Evers et al. unravel the composition of mitochondrial oxidative phosphorylation complexes in P. falciparum asexual and sexual blood stages. Abundance of these complexes differs between both stages, supporting the hypothesis that a mitochondrial metabolic switch is central to gametocyte development and functioning.
- Felix Evers
- , Alfredo Cabrera-Orefice
- & Taco W. A. Kooij
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Article
| Open AccessMaps and metrics of insecticide-treated net access, use, and nets-per-capita in Africa from 2000-2020
Insecticide treated nets (ITNs) are an important part of malaria control in Africa and WHO targets aim for 80% coverage. This study estimates the spatio-temporal access and use of ITNs in Africa from 2000-2020, and shows that both metrics have improved over time but access remains below WHO targets.
- Amelia Bertozzi-Villa
- , Caitlin A. Bever
- & Samir Bhatt
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| Open AccessA single-cell atlas of Plasmodium falciparum transmission through the mosquito
Here the authors use single-cell RNA-seq to profile the transmission stages of the human malaria parasite Plasmodium falciparum as it progresses through the Anopheles mosquito. They highlight unique patterns of gene usage throughout this development and identify potential pleiotropic genes that function at multiple life cycle stages.
- Eliana Real
- , Virginia M. Howick
- & Mara K. N. Lawniczak
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| Open AccessCryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding
In placental malaria, interactions between parasite protein VAR2CSA and human glycosaminoglycan chondroitin sulfate A (CS) sequesters infected red blood cells in the placenta. Here, the authors provide cryo-EM structures of VAR2CSA and placental CS, identifying molecular interactions that could guide design of placental malaria vaccines.
- Kaituo Wang
- , Robert Dagil
- & Ali Salanti
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| Open AccessThe impact of stopping and starting indoor residual spraying on malaria burden in Uganda
Indoor residual spraying (IRS) of insecticide is one of the primary malaria vector control initiatives, but implementation is limited. Here, the authors show that discontinuation of IRS in Uganda was associated with increased malaria incidence, and introduction of IRS was associated with decreased incidence.
- Jane F. Namuganga
- , Adrienne Epstein
- & Isabel Rodriguez-Barraquer
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| Open AccessHeterologous protection against malaria by a simple chemoattenuated PfSPZ vaccine regimen in a randomized trial
In this placebo-controlled trial, 10/13 malaria naïve subjects immunized with a simplified regimen of chemoattenuated P. falciparum sporozoites, PfSPZ-CVac, show sterile protection from heterologous malaria challenge. Immunization was well tolerated and induced high levels of anti-PfCSP antibodies.
- Zita Sulyok
- , Rolf Fendel
- & Peter G. Kremsner
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| Open AccessHigher gametocyte production and mosquito infectivity in chronic compared to incident Plasmodium falciparum infections
In this longitudinal study of an incident (new infections) and chronic (asymptomatic infections) cohort of Plasmodium falciparum infection in children in Burkina Faso, the authors show higher gametocyte production and mosquito infectivity in chronic infections.
- Aissata Barry
- , John Bradley
- & Teun Bousema
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| Open AccessRed blood cell mannoses as phagocytic ligands mediating both sickle cell anaemia and malaria resistance
Red blood cells (RBCs) are phagocytosed in the spleen in sickle cell disease and malaria. Here, Cao et al. show that high mannose N-glycans, exposed on diseased or oxidized RBC surfaces, bind mannose receptor CD206 on host cells, mediating phagocytosis.
- Huan Cao
- , Aristotelis Antonopoulos
- & Mark A. Vickers
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| Open AccessMalaria trends in Ethiopian highlands track the 2000 ‘slowdown’ in global warming
The effect of climate change on highland malaria transmission remains unclear because of increasing and decreasing trends. Here, Rodó et al. analyze malaria case data and climate data for the Ethiopian highlands from 1968 to 2008 and find that changes in temperature and associated climate variability facilitated the effect of interventions at the beginning of the 21st century.
- Xavier Rodó
- , Pamela P. Martinez
- & Mercedes Pascual
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Article
| Open AccessNaturally acquired blocking human monoclonal antibodies to Plasmodium vivax reticulocyte binding protein 2b
Plasmodium vivax reticulocyte binding protein 2b (PvRBP2b) is important for invasion of reticulocytes and PvRBP2b antibodies correlate with protection. Here, Chan et al. isolate and characterize anti-PvRBP2b human monoclonal antibodies and describe mechanisms by which these antibodies inhibit invasion.
- Li-Jin Chan
- , Anugraha Gandhirajan
- & Wai-Hong Tham
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| Open AccessPredicting the public health impact of a malaria transmission-blocking vaccine
Malaria transmission-blocking vaccines are in development, but roll-out strategies have not been assessed. Here, the authors show that transmission-blocking activity is likely to be higher in the field than in laboratory conditions, and that school-aged children are an important group to target.
- Joseph D. Challenger
- , Daniela Olivera Mesa
- & Thomas S. Churcher
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| Open AccessMagneto-optical diagnosis of symptomatic malaria in Papua New Guinea
Here Arndt et al. establish rotating-crystal magneto-optical detection (RMOD) as a near-point-of-care diagnostic tool for malaria detection and report a sensitivity and specificity of 82% and 84%, respectively, as validated by analyzing a clinical population in a high transmission setting in Papua New Guinea.
- L. Arndt
- , T. Koleala
- & S. Karl
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Article
| Open AccessGenotyping cognate Plasmodium falciparum in humans and mosquitoes to estimate onward transmission of asymptomatic infections
Asymptomatic malaria infections contribute to transmission. Here, Sumner et al. infer participant-to-mosquito transmission by sampling naturally-fed mosquitoes from households in Western Kenya and find that asymptomatic infections more than double the odds of transmission to a mosquito compared to symptomatic infections.
- Kelsey M. Sumner
- , Elizabeth Freedman
- & Steve M. Taylor
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Article
| Open AccessStructural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines
Bicyclic azetidine inhibitors are promising antimalarials that target the Plasmodium cytosolic phenylalanine tRNAsynthetase (cFRS). Here, Sharma et al. provide the biochemical and structural basis of its mechanism using co-crystal structure of PvcFRS with BRD1389.
- Manmohan Sharma
- , Nipun Malhotra
- & Amit Sharma
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Article
| Open AccessExposure to pesticides in utero impacts the fetal immune system and response to vaccination in infancy
Control of mosquito populations using pesticides is important for malaria elimination, but effects of pesticides on humans aren’t well understood. Here, Prahl et al. show in a cohort of pregnant Ugandan women and their infants that household spraying with bendiocarb affects the fetal immune system and response to vaccination in infancy.
- Mary Prahl
- , Pamela Odorizzi
- & Margaret E. Feeney
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Article
| Open AccessEfficient population modification gene-drive rescue system in the malaria mosquito Anopheles stephensi
Gene drives may be impeded by the generation of resistant alleles following NHEJ. Here the authors develop a recoded gene-drive rescue system for the malaria mosquito, Anopheles stephensi, that targets the drive to the kynurenine hydroxylase gene for negative selection against mutated alleles.
- Adriana Adolfi
- , Valentino M. Gantz
- & Anthony A. James
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Article
| Open AccessIntegrative genomic analysis reveals mechanisms of immune evasion in P. falciparum malaria
Here, the authors identify signatures of miRNA expression differentiation associated with Plasmodium falciparum infection and parasitemia in a longitudinal pediatric cohort in Burkina Faso. In particular, expression of several miRNAs known to promote lymphocyte cell death is affected during infection.
- Mame Massar Dieng
- , Aïssatou Diawara
- & Youssef Idaghdour
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Article
| Open AccessCaspase-8 mediates inflammation and disease in rodent malaria
Inflammasome activation plays a role in malaria pathogenesis, but details aren’t well understood. Here, the authors show that caspase-8 is a central mediator of systemic inflammation in rodent malaria and that monocytes from malaria patients express active caspases-1, -4 and -8.
- Larissa M. N. Pereira
- , Patrícia A. Assis
- & Ricardo T. Gazzinelli
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| Open AccessAnalysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention
Plasmodium infection activates signaling pathways in a-nucleated erythrocytes. Here, Adderley et al. use a comprehensive antibody microarray to show that infection extensively modulates host cell signalling and that the host receptor tyrosine kinase c-MET supports Plasmodium falciparum proliferation.
- Jack D. Adderley
- , Simona John von Freyend
- & Christian Doerig
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| Open AccessModelling the incremental benefit of introducing malaria screening strategies to antenatal care in Africa
Plasmodium falciparum infection in pregnancy is a major cause of adverse pregnancy outcomes. Here, the authors combine performance estimates of standard rapid diagnostic tests with modelling to assess whether screening at antenatal visits improves upon current intermittent preventative therapy.
- Patrick G. T. Walker
- , Matt Cairns
- & Feiko O. ter Kuile
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Article
| Open AccessDecreased bioefficacy of long-lasting insecticidal nets and the resurgence of malaria in Papua New Guinea
Malaria prevalence in Papua New Guinea has risen in recent years after almost a decade of decline. In this study, the authors demonstrate that long-lasting insecticidal nets used in the country that were manufactured since 2013 have significantly reduced bioefficacy.
- Rebecca Vinit
- , Lincoln Timinao
- & Stephan Karl
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| Open AccessStructure and catalytic regulation of Plasmodium falciparum IMP specific nucleotidase
Plasmodium falciparum IMP-specific 5′-nucleotidase 1 (PfISN1) is of interest as a potential malaria drug target. Here, the authors report that IMP is a substrate, and ATP an allosteric activator, of PfISN1 and present PfISN1 crystal structures in the ligand-free state and bound to either IMP or ATP.
- Loïc Carrique
- , Lionel Ballut
- & Nushin Aghajari
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| Open AccessA microsporidian impairs Plasmodium falciparum transmission in Anopheles arabiensis mosquitoes
Mircobial symbionts of mosquitoes can affect transmission of human pathogens. Here, Herren et al. identify a microsporidian symbiont in Anopheles gambiae that impairs transmission without affecting mosquito fecundity or survival.
- Jeremy K. Herren
- , Lilian Mbaisi
- & Steven P. Sinkins
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| Open AccessThe impact of antimalarial resistance on the genetic structure of Plasmodium falciparum in the DRC
The genome of the malaria parasite Plasmodium falciparum contains a record of past evolutionary forces. Here, using 2537 parasite sequences from the Democratic Republic of the Congo, the authors demonstrate how drug pressure and human movement have shaped the present-day parasite population.
- Robert Verity
- , Ozkan Aydemir
- & Jonathan J. Juliano
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Article
| Open AccessAn intracellular membrane protein GEP1 regulates xanthurenic acid induced gametogenesis of malaria parasites
Mosquito-derived xanthurenic acid (XA) is a trigger for gametogenesis of Plasmodium parasites. Here the authors show that the putative amino acid transporter GEP1 is required for XA-stimulated gametogenesis in Plasmodium yoelii and that it interacts with guanylyl cyclase α (GCα), a cGMP synthesizing enzyme in gametocytes.
- Yuanyuan Jiang
- , Jun Wei
- & Jing Yuan
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Article
| Open AccessDissecting the role of PfAP2-G in malaria gametocytogenesis
The transcription factor PfAP2-G is a key determinant of sexual commitment in Plasmodium falciparum. Here, Josling et al. define the transcriptional regulatory network of PfAP2-G by identifying its DNA binding sites genome-wide, which vary depending on the route of sexual conversion and rely on interactions with the PfAP2-I transcription factor.
- Gabrielle A. Josling
- , Timothy J. Russell
- & Manuel Llinás
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Article
| Open AccessAmplification of Duffy binding protein-encoding gene allows Plasmodium vivax to evade host anti-DBP humoral immunity
Duffy binding protein (DBP) of Plasmodium vivax is important for invasion and is a potential vaccine candidate. Here, the authors show that PvDBP gene amplification protects P vivax in vitro against invasion inhibitory human monoclonal antibodies and is associated to infection of patients with PvDBP binding inhibitory antibodies.
- Jean Popovici
- , Camille Roesch
- & Benoit Witkowski
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Article
| Open AccessInsights into malaria susceptibility using genome-wide data on 17,000 individuals from Africa, Asia and Oceania
Four genome-wide associated loci are currently known for malaria susceptibility. Here, the authors expand on earlier work by combining data from 11 malaria-endemic countries and additional population sequencing informing an African-enriched imputation reference panel, with findings including a previously unreported association on chromosome 6.
- Gavin Band
- , Quang Si Le
- & Dominic P. Kwiatkowski
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| Open AccessMetabolic balancing by miR-276 shapes the mosquito reproductive cycle and Plasmodium falciparum development
Plasmodium growth is adapted to the reproductive cycle of mosquitoes, but underlying mechanisms are unclear. Here, Lampe et al. show that the blood-meal induced miR-276 balances the termination of the mosquito amino acid catabolism and egg development, providing nutrients for Plasmodium sporozoite development.
- Lena Lampe
- , Marius Jentzsch
- & Elena A. Levashina
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Article
| Open AccessResolving the cause of recurrent Plasmodium vivax malaria probabilistically
Relapse, reinfection and recrudescence can all cause recurrent infection after treatment of Plasmodium vivax malaria in endemic areas, but are difficult to distinguish. Here the authors show that they can be differentiated probabilistically and thereby demonstrate the high efficacy of primaquine treatment in preventing relapse.
- Aimee R. Taylor
- , James A. Watson
- & Nicholas J. White
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Article
| Open AccessCis-regulatory CYP6P9b P450 variants associated with loss of insecticide-treated bed net efficacy against Anopheles funestus
Bed nets treated with insecticides have been instrumental in reducing malaria mortality, but insecticide resistance is on the rise. Here, Mugenzi et al. identify genetic variants in the P450 gene CYP6P9b of Anopheles funestus that associate with insecticide resistance and develop a PCR-based diagnostic assay to help identify pyrethroid-resistant strains.
- Leon M. J. Mugenzi
- , Benjamin D. Menze
- & Charles S. Wondji
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| Open AccessAdaptation of Plasmodium falciparum to humans involved the loss of an ape-specific erythrocyte invasion ligand
Here, Proto et al. show that human infective Plasmodium falciparum isolates contain an inactivating mutation in the erythrocyte invasion associated gene PfEBA165, while homologues of ape-infective Laverania species are intact, and that expression of intact PfEBA165 is incompatible with parasite growth in human erythrocytes.
- William R. Proto
- , Sasha V. Siegel
- & Julian C. Rayner
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| Open AccessPotent antibody lineage against malaria transmission elicited by human vaccination with Pfs25
Pfs25 is a transmission-blocking vaccine candidate for Plasmodium. Here, McLeod et al. analyze the antibody response to Pfs25 in sera from a clinical trial evaluating a Pfs25 vaccine candidate, identify a potent transmission-blocking antibody and determine recognized epitopes on Pfs25.
- Brandon McLeod
- , Kazutoyo Miura
- & Jean-Philippe Julien
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| Open AccessPlasmodium vivax chloroquine resistance links to pvcrt transcription in a genetic cross
Here, a cross of Plasmodium vivax malaria parasites links a chloroquine resistance (CQR) phenotype to a 76 kb region of chromosome 1 and greater expression of pvcrt, an ortholog of the Plasmodium falciparum CQR transporter gene.
- Juliana M. Sá
- , Sarah R. Kaslow
- & Thomas E. Wellems
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Article
| Open AccessLung endothelial cell antigen cross-presentation to CD8+T cells drives malaria-associated lung injury
Severe malaria can be associated with respiratory complications. Here, the authors show that malaria-associated pulmonary vascular damage is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8+ T cells induced during infection.
- Carla Claser
- , Samantha Yee Teng Nguee
- & Laurent Renia