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Resistance to malaria through structural variation of red blood cell invasion receptors

CiteULike malaria tags - 19 May 2017 - 6:28pm
Science (18 May 2017), eaam6393, doi:10.1126/science.aam6393
Ellen Leffler, Gavin Band, George Busby, Katja Kivinen, Quang Le, Geraldine Clarke, Kalifa Bojang, David Conway, Muminatou Jallow, Fatoumatta Sisay-Joof, Edith Bougouma, Valentina Mangano, David Modiano, Sodiomon Sirima, Eric Achidi, Tobias Apinjoh, Kevin Marsh, Carolyne Ndila, Norbert Peshu, Thomas Williams, Chris Drakeley, Alphaxard Manjurano, Hugh Reyburn, Eleanor Riley, David Kachala, Malcolm Molyneux, Vysaul Nyirongo, Terrie Taylor, Nicole Thornton, Louise Tilley, Shane Grimsley, Eleanor Drury, Jim Stalker, Victoria Cornelius, Christina Hubbart, Anna Jeffreys, Kate Rowlands, Kirk Rockett, Chris Spencer, Dominic Kwiatkowski, Malaria Genomic Epidemiology Network
Categories: malaria news feeds

Geographic-genetic analysis of Plasmodium falciparum parasite populations from surveys of primary school children in Western Kenya

CiteULike malaria tags - 18 May 2017 - 12:36pm
Wellcome Open Research, Vol. 2 (20 April 2017), 29, doi:10.12688/wellcomeopenres.11228.1
Irene Omedo, Polycarp Mogeni, Kirk Rockett, Alice Kamau, Christina Hubbart, Anna Jeffreys, Lynette Ochola-Oyier, Etienne de Villiers, Caroline Gitonga, Abdisalan Noor, Robert Snow, Dominic Kwiatkowski, Philip Bejon
Categories: malaria news feeds

Artemisinin resistance without pfkelch13 mutations in Plasmodium falciparum isolates from Cambodia

CiteULike malaria tags - 18 May 2017 - 12:30pm
Malaria Journal, Vol. 16, No. 1. (12 May 2017), doi:10.1186/s12936-017-1845-5
Angana Mukherjee, Selina Bopp, Pamela Magistrado, Wesley Wong, Rachel Daniels, Allison Demas, Stephen Schaffner, Chanaki Amaratunga, Pharath Lim, Mehul Dhorda, Olivo Miotto, Charles Woodrow, Elizabeth Ashley, Arjen Dondorp, Nicholas White, Dyann Wirth, Rick Fairhurst, Sarah Volkman
Categories: malaria news feeds

Multiple short windows of Calcium-Dependent Protein Kinase 4 activity coordinate distinct cell cycle events during Plasmodium gametogenesis

CiteULike malaria tags - 11 May 2017 - 10:16am
eLife, Vol. 6 (may 2017), e26524, doi:10.7554/elife.26524

Malaria transmission relies on the production of gametes following ingestion by a mosquito. Here, we show that Ca2+-dependent protein kinase 4 controls three processes essential to progress from a single haploid microgametocyte to the release of eight flagellated microgametes in Plasmodium berghei. A myristoylated isoform is activated by Ca2+ to initiate a first genome replication within twenty seconds of activation. This role is mediated by a protein of the SAPS-domain family involved in S-phase entry. At the same time, CDPK4 is required for the assembly of the subsequent mitotic spindle and to phosphorylate a microtubule-associated protein important for mitotic spindle formation. Finally, a non-myristoylated isoform is essential to complete cytokinesis by activating motility of the male flagellum. This role has been linked to phosphorylation of an uncharacterised flagellar protein. Altogether, this study reveals how a kinase integrates and transduces multiple signals to control key cell-cycle transitions during Plasmodium gametogenesis.
Hanwei Fang, Natacha Klages, Bastien Baechler, Evelyn Hillner, Lu Yu, Mercedes Pardo, Jyoti Choudhary, Mathieu Brochet
Categories: malaria news feeds

Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase

CiteULike malaria tags - 4 May 2017 - 11:50am
Science Translational Medicine, Vol. 9, No. 387. (26 April 2017), eaad9735, doi:10.1126/scitranslmed.aad9735
Tanya Paquet, Claire Le Manach, Diego Cabrera, Yassir Younis, Philipp Henrich, Tara Abraham, Marcus Lee, Rajshekhar Basak, Sonja Ghidelli-Disse, María Lafuente-Monasterio, Marcus Bantscheff, Andrea Ruecker, Andrew Blagborough, Sara Zakutansky, Anne-Marie Zeeman, Karen White, David Shackleford, Janne Mannila, Julia Morizzi, Christian Scheurer, Iñigo Angulo-Barturen, María Martínez, Santiago Ferrer, Laura Sanz, Francisco Gamo, Janette Reader, Mariette Botha, Koen Dechering, Robert Sauerwein, Anchalee Tungtaeng, Pattaraporn Vanachayangkul, Chek Lim, Jeremy Burrows, Michael Witty, Kennan Marsh, Christophe Bodenreider, Rosemary Rochford, Suresh Solapure, María Jiménez-Díaz, Sergio Wittlin, Susan Charman, Cristina Donini, Brice Campo, Lyn-Marie Birkholtz, Kirsten Hanson, Gerard Drewes, Clemens Kocken, Michael Delves, Didier Leroy, David Fidock, David Waterson, Leslie Street, Kelly Chibale
Categories: malaria news feeds

Asymptomatic Plasmodium vivax infections induce robust IgG responses to multiple blood-stage proteins in a low-transmission region of western Thailand

CiteULike malaria tags - 4 May 2017 - 11:33am
Malaria Journal, Vol. 16, No. 1. (28 April 2017), doi:10.1186/s12936-017-1826-8
Rhea Longley, Camila França, Michael White, Chalermpon Kumpitak, Patiwat Sa-angchai, Jakub Gruszczyk, Jessica Hostetler, Anjali Yadava, Christopher King, Rick Fairhurst, Julian Rayner, Wai-Hong Tham, Wang Nguitragool, Jetsumon Sattabongkot, Ivo Mueller
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Genomic Characterization of Recrudescent Plasmodium malariae after Treatment with Artemether/Lumefantrine

CiteULike malaria tags - 27 April 2017 - 10:03am
Emerging Infectious Diseases, Vol. 23, No. 8. (August 2017), doi:10.3201/eid2308.161582
Gavin Rutledge, Ian Marr, Huang, Sarah Auburn, Jutta Marfurt, Mandy Sanders, Nicholas White, Matthew Berriman, Chris Newbold, Nicholas Anstey, Thomas Otto, Ric Price
Categories: malaria news feeds

Insecticide-induced leg loss does not eliminate biting and reproduction in Anopheles gambiae mosquitoes

CiteULike malaria tags - 27 April 2017 - 9:23am
Scientific Reports, Vol. 7 (25 April 2017), 46674, doi:10.1038/srep46674
Alison Isaacs, Amy Lynd, Martin Donnelly
Categories: malaria news feeds

Massive introgression drives species radiation at the range limit of Anopheles gambiae

CiteULike malaria tags - 20 April 2017 - 10:50am
Scientific Reports, Vol. 7 (18 April 2017), 46451, doi:10.1038/srep46451
José Vicente, Christopher Clarkson, Beniamino Caputo, Bruno Gomes, Marco Pombi, Carla Sousa, Tiago Antao, João Dinis, Giordano Bottà, Emiliano Mancini, Vincenzo Petrarca, Daniel Mead, Eleanor Drury, James Stalker, Alistair Miles, Dominic Kwiatkowski, Martin Donnelly, Amabélia Rodrigues, Alessandra Torre, David Weetman, João Pinto
Categories: malaria news feeds

Capturing in vivo RNA transcriptional dynamics from the malaria parasite Plasmodium falciparum

CiteULike malaria tags - 20 April 2017 - 10:06am
Genome Research (17 April 2017), gr.217356.116, doi:10.1101/gr.217356.116

An international, peer-reviewed genome sciences journal featuring outstanding original research that offers novel insights into the biology of all organisms
Heather Painter, Manuela Carrasquilla, Manuel Llinás
Categories: malaria news feeds

Shared Consensus Machine Learning Models for Predicting Blood Stage Malaria Inhibition

CiteULike malaria tags - 13 April 2017 - 8:56am
J. Chem. Inf. Model., Vol. 57, No. 3. (27 March 2017), pp. 445-453, doi:10.1021/acs.jcim.6b00572

The development of new antimalarial therapies is essential, and lowering the barrier of entry for the screening and discovery of new lead compound classes can spur drug development at organizations that may not have large compound screening libraries or resources to conduct high-throughput screens. Machine learning models have been long established to be more robust and have a larger domain of applicability with larger training sets. Screens over multiple data sets to find compounds with potential malaria blood stage inhibitory activity have been used to generate multiple Bayesian models. Here we describe a method by which Bayesian quantitative structure–activity relationship models, which contain information on thousands to millions of proprietary compounds, can be shared between collaborators at both for-profit and not-for-profit institutions. This model-sharing paradigm allows for the development of consensus models that have increased predictive power over any single model and yet does not reveal the identity of any compounds in the training sets.
Andreas Verras, Chris Waller, Peter Gedeck, Darren Green, Thierry Kogej, Anandkumar Raichurkar, Manoranjan Panda, Anang Shelat, Julie Clark, Kiplin Guy, George Papadatos, Jeremy Burrows
Categories: malaria news feeds

Challenges for achieving safe and effective radical cure of Plasmodium vivax: a round table discussion of the APMEN Vivax Working Group

CiteULike malaria tags - 12 April 2017 - 12:10pm
Malaria Journal, Vol. 16, No. 1. (5 April 2017), doi:10.1186/s12936-017-1784-1
Kamala Thriemer, Benedikt Ley, Albino Bobogare, Lek Dysoley, Mohammad Alam, Ayodhia Pasaribu, Jetsumon Sattabongkot, Elodie Jambert, Gonzalo Domingo, Robert Commons, Sarah Auburn, Jutta Marfurt, Angela Devine, Mohammad Aktaruzzaman, Nayeem Sohel, Rinzin Namgay, Tobgyel Drukpa, Surender Sharma, Elvieda Sarawati, Iriani Samad, Minerva Theodora, Simone Nambanya, Sonesay Ounekham, Rose Mudin, Garib Da Thakur, Leo Makita, Raffy Deray, Sang-Eun Lee, Leonard Boaz, Manjula Danansuriya, Santha Mudiyanselage, Nipon Chinanonwait, Suravadee Kitchakarn, Johnny Nausien, Esau Naket, Thang Duc, Ha Do Manh, Young Hong, Qin Cheng, Jack Richards, Rita Kusriastuti, Ari Satyagraha, Rintis Noviyanti, Xavier Ding, Wasif Khan, Ching Swe Phru, Zhu Guoding, Gao Qi, Akira Kaneko, Olivo Miotto, Wang Nguitragool, Wanlapa Roobsoong, Katherine Battle, Rosalind Howes, Arantxa Roca-Feltrer, Stephan Duparc, Ipsita Bhowmick, Enny Kenangalem, Jo-Anne Bibit, Alyssa Barry, David Sintasath, Rabindra Abeyasinghe, Carol Sibley, James McCarthy, Lorenz von Seidlein, Kevin Baird, Ric Price
Categories: malaria news feeds

Sub-minute phosphoregulation of cell-cycle systems during Plasmodium gamete formation revealed by a high-resolution time course

CiteULike malaria tags - 12 April 2017 - 10:04am
bioRxiv (10 April 2017), 126276, doi:10.1101/126276

bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution
Brandon Invergo, Mathieu Brochet, Lu Yu, Jyoti Choudhary, Pedro Beltrao, Oliver Billker
Categories: malaria news feeds

Genetic diversity of next generation antimalarial targets: A baseline for drug resistance surveillance programmes

CiteULike malaria tags - 5 April 2017 - 9:41am
International Journal for Parasitology: Drugs and Drug Resistance, Vol. 7, No. 2. (August 2017), pp. 174-180, doi:10.1016/j.ijpddr.2017.03.001

Genetic diversity of 11gene-targets of new antimalarial compounds was investigated. Genetic data was analysed for 18 malaria endemic countries. No signals of selective pressure was observed. A mutation linked to resistance to a new antimalarial was found in African parasites. Amino-acid changes close to reported antimalarial resistant mutations were detected. Drug resistance is a recurrent problem in the fight against malaria. Genetic and epidemiological surveillance of antimalarial resistant parasite alleles is crucial to guide drug therapies and clinical management. New antimalarial compounds are currently at various stages of clinical trials and regulatory evaluation. Using ∼2000 Plasmodium falciparum genome sequences, we investigated the genetic diversity of eleven gene-targets of promising antimalarial compounds and assessed their potential efficiency across malaria endemic regions. We determined if the loci are under selection prior to the introduction of new drugs and established a baseline of genetic variance, including potential resistant alleles, for future surveillance programmes.
Ana Gomes, Matt Ravenhall, Ernest Benavente, Arthur Talman, Colin Sutherland, Cally Roper, Taane Clark, Susana Campino
Categories: malaria news feeds

A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue.

CiteULike malaria tags - 23 March 2017 - 1:37pm
Nature communications, Vol. 8 (06 March 2017)

Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg(-1), respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target.
Ebere Sonoiki, Caroline Ng, Marcus Lee, Denghui Guo, Yong-Kang Zhang, Yasheen Zhou, MR Alley, Vida Ahyong, Laura Sanz, Maria Jose Lafuente-Monasterio, Chen Dong, Patrick Schupp, Jiri Gut, Jenny Legac, Roland Cooper, Francisco-Javier Gamo, Joseph DeRisi, Yvonne Freund, David Fidock, Philip Rosenthal
Categories: malaria news feeds

A Surface Phospholipase Is Involved in the Migration of Plasmodium Sporozoites through Cells

CiteULike malaria tags - 20 March 2017 - 10:28pm
Journal of Biological Chemistry, Vol. 280, No. 8. (25 February 2005), pp. 6752-6760, doi:10.1074/jbc.m411465200

Plasmodium sporozoites, injected by mosquitoes into the skin of the host, traverse cells during their migration to hepatocytes where they continue their life cycle. The mechanisms used by the parasite to rupture the plasma membrane of the host cells are not known. Here we report the presence of a phospholipase on the surface of Plasmodium berghei sporozoites (P. berghei phospholipase; Pb PL) and demonstrate that it is involved in the establishment of a malaria infection in vivo. Pb PL is highly conserved among the Plasmodium species. The protein is about 750 amino acids, with a predicted signal sequence and a carboxyl terminus that is 32% identical to the vertebrate lecithin:cholesterol acyltransferase, a secreted phospholipase. Pb PL contains a motif characteristic of lipases and a catalytic triad of a serine, aspartate, and histidine that is found in several phospholipases. We have verified its lipase and membrane lytic activity in vitro, using recombinant baculovirus-expressed protein. To study its role in vivo, we have disrupted the P. berghei PL open reading frame and generated mutants in its active site. During an infection through mosquito bite, the infectivity of the knock-out parasites in the liver is decreased by ∼90%. The prepatent period of the resulting blood infection is 1 day longer as compared with wild type. Further, the mutant sporozoites are impaired in their ability to cross epithelial cell layers. Thus, the Pb PL functions as a lipase to damage cell membranes and facilitates sporozoite passage through cells during their migration from the skin to the bloodstream.
Purnima Bhanot, Kristine Schauer, Isabelle Coppens, Victor Nussenzweig
Categories: malaria news feeds

Genetic diversity of next generation antimalarial targets: A baseline for drug resistance surveillance programmes

CiteULike malaria tags - 20 March 2017 - 12:35pm
International Journal for Parasitology: Drugs and Drug Resistance (March 2017), doi:10.1016/j.ijpddr.2017.03.001

Genetic diversity of 11gene-targets of new antimalarial compounds was investigated. Genetic data was analyzed for 18 malaria endemic countries. No signals of selective pressure was observed. A mutation linked to resistance to a new antimalarial was found in African parasites. Amino-acid changes close to reported antimalarial resistant mutations were detected. Drug resistance is a recurrent problem in the fight against malaria. Genetic and epidemiological surveillance of antimalarial resistant parasite alleles is crucial to guide drug therapies and clinical management. New antimalarial compounds are currently at various stages of clinical trials and regulatory evaluation. Using ∼2000 Plasmodium falciparum genome sequences, we investigated the genetic diversity of eleven gene-targets of promising antimalarial compounds and assessed their potential efficiency across malaria endemic regions. We determined if the loci are under selection prior to the introduction of new drugs and established a baseline of genetic variance, including potential resistant alleles, for future surveillance programmes.
Ana Gomes, Matt Ravenhall, Ernest Benavente, Arthur Talman, Colin Sutherland, Cally Roper, Taane Clark, Susana Campino
Categories: malaria news feeds

Migration through host cells activates Plasmodium sporozoites for infection

CiteULike malaria tags - 17 March 2017 - 1:41pm
Nature Medicine, Vol. 8, No. 11. (15 October 2002), pp. 1318-1322, doi:10.1038/nm785

Plasmodium sporozoites, the infective stage of the malaria parasite transmitted by mosquitoes, migrate through several hepatocytes before infecting a final one. Migration through hepatocytes occurs by breaching their plasma membranes, and final infection takes place with the formation of a vacuole around the sporozoite1. Once in the liver, sporozoites have already reached their target cells, making migration through hepatocytes prior to infection seem unnecessary. Here we show that this migration is required for infection of hepatocytes. Migration through host cells, but not passive contact with hepatocytes, induces the exocytosis of sporozoite apical organelles, a prerequisite for infection with formation of a vacuole. Sporozoite activation induced by migration through host cells is an essential step of Plasmodium life cycle.
Maria Mota, Julius Hafalla, Ana Rodriguez
Categories: malaria news feeds

Micro-epidemiological structuring of Plasmodium falciparum parasite populations in regions with varying transmission intensities in Africa.

CiteULike malaria tags - 2 March 2017 - 11:51am
Wellcome Open Research, Vol. 2 (14 February 2017), 10, doi:10.12688/wellcomeopenres.10784.1
Irene Omedo, Polycarp Mogeni, Teun Bousema, Kirk Rockett, Alfred Amambua-Ngwa, Isabella Oyier, Stevenson, Baidjoe, Etienne de Villiers, Greg Fegan, Amanda Ross, Christina Hubbart, Anne Jeffreys, Williams, Dominic Kwiatkowski, Philip Bejon
Categories: malaria news feeds

Sterile protection against human malaria by chemoattenuated PfSPZ vaccine

CiteULike malaria tags - 23 February 2017 - 11:19am
Nature, Vol. 542, No. 7642. (15 February 2017), pp. 445-449, doi:10.1038/nature21060

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). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ (PfSPZ Challenge) to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac). Three doses of 5.12 × 104 PfSPZ of PfSPZ Challenge at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 × 103 (group I) or 1.28 × 104 (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 × 104 PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.
Benjamin Mordmüller, Güzin Surat, Heimo Lagler, Sumana Chakravarty, Andrew Ishizuka, Albert Lalremruata, Markus Gmeiner, Joseph Campo, Meral Esen, Adam Ruben, Jana Held, Carlos Calle, Juliana Mengue, Tamirat Gebru, Javier Ibáñez, Mihály Sulyok, Eric James, Peter Billingsley, KC Natasha, Anita Manoj, Tooba Murshedkar, Anusha Gunasekera, Abraham Eappen, Tao Li, Richard Stafford, Minglin Li, Phil Felgner, Robert Seder, Thomas Richie, Sim, Stephen Hoffman, Peter Kremsner
Categories: malaria news feeds

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