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https://www.readbyqxmd.com/read/28211852/plasmodium-falciparum-crk4-directs-continuous-rounds-of-dna-replication-during-schizogony
#1
Markus Ganter, Jonathan M Goldberg, Jeffrey D Dvorin, Joao A Paulo, Jonas G King, Abhai K Tripathi, Aditya S Paul, Jing Yang, Isabelle Coppens, Rays H Y Jiang, Brendan Elsworth, David A Baker, Rhoel R Dinglasan, Steven P Gygi, Manoj T Duraisingh
Plasmodium parasites, the causative agents of malaria, have evolved a unique cell division cycle in the clinically relevant asexual blood stage of infection(1). DNA replication commences approximately halfway through the intracellular development following invasion and parasite growth. The schizont stage is associated with multiple rounds of DNA replication and nuclear division without cytokinesis, resulting in a multinucleated cell. Nuclei divide asynchronously through schizogony, with only the final round of DNA replication and segregation being synchronous and coordinated with daughter cell assembly(2,3)...
February 17, 2017: Nature Microbiology
https://www.readbyqxmd.com/read/28211535/arylmethylamino-steroids-as-antiparasitic-agents
#2
Reimar Krieg, Esther Jortzik, Alice-Anne Goetz, Stéphanie Blandin, Sergio Wittlin, Mourad Elhabiri, Mahsa Rahbari, Selbi Nuryyeva, Kerstin Voigt, Hans-Martin Dahse, Axel Brakhage, Svenja Beckmann, Thomas Quack, Christoph G Grevelding, Anthony B Pinkerton, Bruno Schönecker, Jeremy Burrows, Elisabeth Davioud-Charvet, Stefan Rahlfs, Katja Becker
In search of antiparasitic agents, we here identify arylmethylamino steroids as potent compounds and characterize more than 60 derivatives. The lead compound 1o is fast acting and highly active against intraerythrocytic stages of chloroquine-sensitive and resistant Plasmodium falciparum parasites (IC50 1-5 nM) as well as against gametocytes. In P. berghei-infected mice, oral administration of 1o drastically reduces parasitaemia and cures the animals. Furthermore, 1o efficiently blocks parasite transmission from mice to mosquitoes...
February 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28203236/the-deubiquitinating-enzyme-cylindromatosis-dampens-cd8-t-cell-responses-and-is-a-critical-factor-for-experimental-cerebral-malaria-and-blood-brain-barrier-damage
#3
Ursula Schmid, Werner Stenzel, Josephin Koschel, Maria Raptaki, Xu Wang, Michael Naumann, Kai Matuschewski, Dirk Schlüter, Gopala Nishanth
Cerebral malaria is a severe complication of human malaria and may lead to death of Plasmodium falciparum-infected individuals. Cerebral malaria is associated with sequestration of parasitized red blood cells within the cerebral microvasculature resulting in damage of the blood-brain barrier and brain pathology. Although CD8(+) T cells have been implicated in the development of murine experimental cerebral malaria (ECM), several other studies have shown that CD8(+) T cells confer protection against blood-stage infections...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28203097/cerebral-malaria-insight-into-pathogenesis-complications-and-molecular-biomarkers
#4
Farah Hafiz Yusuf, Muhammad Yusuf Hafiz, Maria Shoaib, Syed Ahsanuddin Ahmed
Cerebral malaria is a medical emergency. All patients with Plasmodium falciparum malaria with neurologic manifestations of any degree should be urgently treated as cases of cerebral malaria. Pathogenesis of cerebral malaria is due to damaged vascular endothelium by parasite sequestration, inflammatory cytokine production and vascular leakage, which result in brain hypoxia, as indicated by increased lactate and alanine concentrations. The levels of the biomarkers' histidine-rich protein II, angiopoietin-Tie-2 system and plasma osteoprotegrin serve as diagnostic and prognostic markers...
2017: Infection and Drug Resistance
https://www.readbyqxmd.com/read/28202065/alternative-transmission-routes-in-the-malaria-elimination-era-an-overview-of-transfusion-transmitted-malaria-in-the-americas
#5
Regina M Alho, Kim Vinícius Amaral Machado, Fernando F A Val, Nelson A Fraiji, Marcia A A Alexandre, Gisely C Melo, Judith Recht, André M Siqueira, Wuelton M Monteiro, Marcus V G Lacerda
BACKGROUND: Transfusion-transmitted (TT) malaria is an alternative infection route that has gained little attention from authorities, despite representing a life-threatening condition. There has been no systematic review of this health problem in American countries. The aim of this study was to describe the clinical and epidemiological characteristics of TT malaria in the Americas and identify factors associated with lethality based on the studies published in the literature. METHODS: Potentially relevant papers in all languages were retrieved from MEDLINE and LILACS...
February 15, 2017: Malaria Journal
https://www.readbyqxmd.com/read/28202027/a-novel-pfs38-protein-complex-on-the-surface-of-plasmodium-falciparum-blood-stage-merozoites
#6
Gourab Paul, Arunaditya Deshmukh, Inderjeet Kaur, Sumit Rathore, Surbhi Dabral, Ashutosh Panda, Susheel Kumar Singh, Asif Mohmmed, Michael Theisen, Pawan Malhotra
BACKGROUND: The Plasmodium genome encodes for a number of 6-Cys proteins that contain a module of six cysteine residues forming three intramolecular disulphide bonds. These proteins have been well characterized at transmission as well as hepatic stages of the parasite life cycle. In the present study, a large complex of 6-Cys proteins: Pfs41, Pfs38 and Pfs12 and three other merozoite surface proteins: Glutamate-rich protein (GLURP), SERA5 and MSP-1 were identified on the Plasmodium falciparum merozoite surface...
February 16, 2017: Malaria Journal
https://www.readbyqxmd.com/read/28201964/plasmodium-falciparum-heat-shock-protein-70-lacks-immune-modulatory-activity
#7
AOfentse Jacob Pooe, Gabriele Köllisch, Holger Heine, Addmore Shonhai
Heat shock protein 70 (Hsp70) family are conserved molecules that constitute a major part of the cell's protein folding machinery. The role of Hsp70s of parasitic origin in host cell immune modulation has remained contentious. This is largely due to the fact that several studies implicating Hsp70 in immune modulation rely on the use of recombinant protein derived from bacteria which is often fraught contamination. Thus, in the current study, we expressed recombinant Plasmodium falciparum Hsp70 (PfHsp70) using in three bacterial expression hosts: E...
February 14, 2017: Protein and Peptide Letters
https://www.readbyqxmd.com/read/28199305/sterile-protection-against-human-malaria-by-chemoattenuated-pfspz-vaccine
#8
Benjamin Mordmüller, Güzin Surat, Heimo Lagler, Sumana Chakravarty, Andrew S Ishizuka, Albert Lalremruata, Markus Gmeiner, Joseph J Campo, Meral Esen, Adam J Ruben, Jana Held, Carlos Lamsfus Calle, Juliana B Mengue, Tamirat Gebru, Javier Ibáñez, Mihály Sulyok, Eric R James, Peter F Billingsley, K C Natasha, Anita Manoj, Tooba Murshedkar, Anusha Gunasekera, Abraham G Eappen, Tao Li, Richard E Stafford, Minglin Li, Phil L Felgner, Robert A Seder, Thomas L Richie, B Kim Lee Sim, Stephen L Hoffman, Peter G Kremsner
A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites. A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes; by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ ('PfSPZ Vaccine'); or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine or mefloquine (chemoprophylaxis with sporozoites)...
February 15, 2017: Nature
https://www.readbyqxmd.com/read/28198449/recombinant-vacuolar-iron-transporter-family-homologue-pfvit-from-human-malaria-causing-plasmodium-falciparum-is-a-fe-2-h-exchanger
#9
Paola Labarbuta, Katie Duckett, Catherine H Botting, Osama Chahrour, John Malone, John P Dalton, Christopher J Law
Vacuolar iron transporters (VITs) are a poorly understood family of integral membrane proteins that can function in iron homeostasis via sequestration of labile Fe(2+) into vacuolar compartments. Here we report on the heterologous overexpression and purification of PfVIT, a vacuolar iron transporter homologue from the human malaria-causing parasite Plasmodium falciparum. Use of synthetic, codon-optimised DNA enabled overexpression of functional PfVIT in the inner membrane of Escherichia coli which, in turn, conferred iron tolerance to the bacterial cells...
February 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28197312/identification-and-mechanistic-evaluation-of-hemozoin-inhibiting-triarylimidazoles-active-against-plasmodium-falciparum
#10
Kathryn J Wicht, Jill M Combrinck, Peter J Smith, Roger Hunter, Timothy J Egan
In a previous study, target based screening was carried out for inhibitors of β-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active against Plasmodium falciparum. Here, we report the subsequent synthesis and testing of derivatives with varying substituents on the three phenyl rings for this series. The results indicated that a 2-hydroxy-1,3-dimethoxy substitution pattern on ring A is required for submicromolar parasite activity. In addition, cell-fractionation studies revealed uncommonly large, dose-dependent increases of P...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28196536/community-engagement-and-the-social-context-of-targeted-malaria-treatment-a-qualitative-study-in-kayin-karen-state-myanmar
#11
Kate Sahan, Christopher Pell, Frank Smithuis, Aung Kyaw Phyo, Sai Maung Maung, Chanida Indrasuta, Arjen M Dondorp, Nicholas J White, Nicholas P J Day, Lorenz von Seidlein, Phaik Yeong Cheah
BACKGROUND: The spread of artemisinin-resistance in Plasmodium falciparum is a threat to current global malaria control initiatives. Targeted malaria treatment (TMT), which combines mass anti-malarial administration with conventional malaria prevention and control measures, has been proposed as a strategy to tackle this problem. The effectiveness of TMT depends on high levels of population coverage and is influenced by accompanying community engagement activities and the local social context...
February 14, 2017: Malaria Journal
https://www.readbyqxmd.com/read/28195530/structural-basis-for-inhibition-of-erythrocyte-invasion-by-antibodies-to-plasmodium-falciparum-protein-cyrpa
#12
Lin Chen, Yibin Xu, Wilson Wong, Jennifer K Thompson, Julie Healer, Ethan Goddard-Borger, Michael C Lawrence, Alan F Cowman
Plasmodium falciparum causes malaria in humans with over 450,000 deaths annually. The asexual blood stage involves invasion of erythrocytes by merozoites, in which they grow and divide to release daughter merozoites, which in turn invade new erythrocytes perpetuating the cycle responsible for malaria. A key step in merozoite invasion is the essential binding of PfRh5/CyRPA/PfRipr complex to basigin, a step linked to formation of a pore between merozoites and erythrocytes. We show CyRPA interacts directly with PfRh5...
February 14, 2017: ELife
https://www.readbyqxmd.com/read/28195463/target-elucidation-by-co-crystal-structures-of-nadh-ubiquinone-oxidoreductase-of-plasmodium-falciparum-pfndh2-with-small-molecule-to-eliminate-drug-resistant-malaria
#13
Yiqing Yang, You Yu, Xiaolu Li, Jing Li, Yue Wu, Jie Yu, Jingpeng Ge, Zhenghui Huang, Lubin Jiang, Yu Rao, Maojun Yang
Drug-resistant malarial strains have been continuously emerging recently, which posts a great challenge for the global health. Therefore, new anti-malarial drugs with novel targeting mechanisms are urgently needed for fighting drug-resistant malaria. NADH-ubiquinone oxidoreductase of Plasmodium falciparum (PfNDH2) represents a viable target for anti-malarial drug development. However, the absence of structural information of PfNDH2 limited rational drug design and further development. Herein, we report high resolution crystal structures of the PfNDH2 protein for the first time in Apo-, NADH- and RYL-552 (a new inhibitor)-bound states...
February 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28195038/structure-of-the-malaria-vaccine-candidate-antigen-cyrpa-and-its-complex-with-a-parasite-invasion-inhibitory-antibody
#14
Paola Favuzza, Elena Guffart, Marco Tamborrini, Bianca Scherer, Anita M Dreyer, Arne C Rufer, Johannes Erny, Joerg Hoernschemeyer, Ralf Thoma, Georg Schmid, Bernard Gsell, Araceli Lamelas, Joerg Benz, Catherine Joseph, Hugues Matile, Gerd Pluschke, Markus G Rudolph
Invasion of erythrocytes by Plasmodial merozoites is a composite process involving the interplay of several proteins. Among them, the Plasmodium falciparum Cysteine-Rich Protective Antigen (PfCyRPA) is a crucial component of a ternary complex, including Reticulocyte binding-like Homologous protein 5 (PfRH5) and the RH5-interacting protein (PfRipr), essential for erythrocyte invasion. Here we present the crystal structure of PfCyRPA and of its complex with the antigen-binding fragment of a parasite growth inhibitory antibody...
February 14, 2017: ELife
https://www.readbyqxmd.com/read/28194431/polyfunctional-and-ifn-%C3%AE-monofunctional-human-cd4-t-cell-populations-are-molecularly-distinct
#15
Julie G Burel, Simon H Apte, Penny L Groves, James S McCarthy, Denise L Doolan
Pathogen-specific polyfunctional T cell responses have been associated with favorable clinical outcomes, but it is not known whether molecular differences exist between polyfunctional and monofunctional cytokine-producing T cells. Here, we report that polyfunctional CD4(+) T cells induced during Plasmodiumfalciparum (P. falciparum) blood-stage infection in humans have a unique transcriptomic profile compared with IFN-γ monofunctional CD4(+) T cells and, thus, are molecularly distinct. The 14-gene signature revealed in P...
February 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28193898/systems-analysis-of-protective-immune-responses-to-rts-s-malaria-vaccination-in-humans
#16
Dmitri Kazmin, Helder I Nakaya, Eva K Lee, Matthew J Johnson, Robbert van der Most, Robert A van den Berg, W Ripley Ballou, Erik Jongert, Ulrike Wille-Reece, Christian Ockenhouse, Alan Aderem, Daniel E Zak, Jerald Sadoff, Jenny Hendriks, Jens Wrammert, Rafi Ahmed, Bali Pulendran
RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium-infected mosquitoes, 3 wk after the final immunization, resulted in ∼50% protection in both groups of vaccinees...
February 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28193740/development-of-delayed-hemolytic-anemia-after-treatment-with-oral-artemether-lumefantrine-in-two-patients-with-severe-falciparum-malaria
#17
Yasuhiro Tsuchido, Fukumi Nakamura-Uchiyama, Kasumi Toyoda, Moritoshi Iwagami, Kentaro Tochitani, Koh Shinohara, Naokuni Hishiya, Taku Ogawa, Kenji Uno, Kei Kasahara, Yukiteru Ouji, Shigeyuki Kano, Keiichi Mikasa, Tsunehiro Shimizu, Masahide Yoshikawa, Haruhiko Maruyama
Recently, reports of delayed hemolytic anemia after treatment with artemisinin and its derivatives have emerged. Here we report two cases of delayed hemolytic anemia in a patient with severe falciparum malaria after treatment with oral artemether-lumefantrine (AL). The first patient, a 20-year-old Japanese male student, was diagnosed with falciparum malaria and was administered AL. As having a high parasitemia rate (20.6%) was the only severe malaria criterion met in this case and his general condition was stable, we continued with AL treatment...
February 13, 2017: American Journal of Tropical Medicine and Hygiene
https://www.readbyqxmd.com/read/28193646/simplified-reversed-chloroquines-to-overcome-malaria-resistance-to-quinoline-based-drugs
#18
Bornface Gunsaru, Steven J Burgess, Westin Morrill, Jane X Kelly, Shawheen Shomloo, Martin J Smilkstein, Katherine Liebmann, David H Peyton
Building on our earlier work of attaching a chemosensitizer (reversal agent) to a known drug pharmacophore, we have now expanded the structure-activity relationship study to include simplified versions of the chemosensitizer. The change from two aromatic rings in this head group to a single ring, in fact, does not appear to detrimentally affect the antimalarial activity of the compounds. Data from in vitro heme binding and β-hematin inhibition assays suggest that the single aromatic RCQ compounds retain similar activities against P...
February 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28192523/bead-based-immunoassay-allows-sub-picogram-detection-of-histidine-rich-protein-2-from-plasmodium-falciparum-and-estimates-reliability-of-malaria-rapid-diagnostic-tests
#19
Eric Rogier, Mateusz Plucinski, Naomi Lucchi, Kimberly Mace, Michelle Chang, Jean Frantz Lemoine, Baltazar Candrinho, James Colborn, Rafael Dimbu, Filomeno Fortes, Venkatachalam Udhayakumar, John Barnwell
Detection of histidine-rich protein 2 (HRP2) from the malaria parasite Plasmodium falciparum provides evidence for active or recent infection, and is utilized for both diagnostic and surveillance purposes, but current laboratory immunoassays for HRP2 are hindered by low sensitivities and high costs. Here we present a new HRP2 immunoassay based on antigen capture through a bead-based system capable of detecting HRP2 at sub-picogram levels. The assay is highly specific and cost-effective, allowing fast processing and screening of large numbers of samples...
2017: PloS One
https://www.readbyqxmd.com/read/28192434/adverse-effects-of-mefloquine-for-the-treatment-of-uncomplicated-malaria-in-thailand-a-pooled-analysis-of-19-850-individual-patients
#20
Sue J Lee, Feiko O Ter Kuile, Ric N Price, Christine Luxemburger, François Nosten
Mefloquine (MQ) has been used for the treatment of malaria since the mid-1980s, first as monotherapy or as fixed combination with sulfadoxine-pyrimethamine (MSP) and since the mid-1990s in combination with artesunate. There is a renewed interested in MQ as part of a triple therapy for the treatment of multi-drug resistance P. falciparum malaria. The widespread use of MQ beyond south-East Asia has been constrained by reports of poor tolerability. Here we present the side effect profile of MQ for the treatment of uncomplicated malaria on the Thai-Myanmar/Cambodia borders...
2017: PloS One
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