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Quantitative Seq-LGS: Genome-Wide Identification of Genetic Drivers of Multiple Phenotypes in Malaria Parasites

CiteULike malaria tags - 13 October 2016 - 11:59am
bioRxiv (30 September 2016), 078451, doi:10.1101/078451

bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution
Hussein Abkallo, Axel Martinelli, Megumi Inoue, Abhinay Ramaprasad, Phonepadith Xangsayarath, Jesse Gitaka, Jianxia Tang, Kazuhide Yahata, Augustin Zoungrana, Hayato Mitaka, Paul Hunt, Richard Carter, Osamu Kaneko, Ville Mustonen, Christopher Illingworth, Arnab Pain, Richard Culleton
Categories: malaria news feeds

Genome-wide association analysis identifies genetic loci associated with resistance to multiple antimalarials in Plasmodium falciparum from China-Myanmar border

CiteULike malaria tags - 7 October 2016 - 11:11am
Scientific Reports, Vol. 6 (3 October 2016), 33891, doi:10.1038/srep33891
Zenglei Wang, Mynthia Cabrera, Jingyun Yang, Lili Yuan, Bhavna Gupta, Xiaoying Liang, Karen Kemirembe, Sony Shrestha, Awtum Brashear, Xiaolian Li, Stephen Porcella, Jun Miao, Zhaoqing Yang, Xin-zhuan Su, Liwang Cui
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A computational lens for sexual-stage transmission, reproduction, fitness and kinetics in Plasmodium falciparum

CiteULike malaria tags - 29 September 2016 - 12:03pm
Malaria Journal, Vol. 15, No. 1. (21 September 2016), doi:10.1186/s12936-016-1538-5
Mara Lawniczak, Philip Eckhoff
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Characterisation of Plasmodium invasive organelles; an ookinete microneme proteome

CiteULike malaria tags - 19 September 2016 - 1:32pm
Proteomics, Vol. 9, No. 5. (1 March 2009), pp. 1142-1151, doi:10.1002/pmic.200800404

Secretion of microneme proteins is essential to Plasmodium invasion but the molecular composition of these secretory organelles remains poorly defined. Here, we describe the first Plasmodium microneme proteome. Purification of micronemes by subcellular fractionation from cultured ookinetes was confirmed by enrichment of known micronemal proteins and electron microscopy. Quantitation of electron micrographs showed >14-fold microneme enrichment compared to the intact ookinete, such that micronemes comprised 85% of the identifiable organelles in the fraction. Gel LC-MS/MS of the most abundant protein constituents of the fraction identified three known micronemal proteins chitinase, CTRP, SOAP, together with protein disulphide isomerase (PDI) and HSP70. Highly sensitive MudPIT shotgun proteomics described a total of 345 proteins in the fraction. M1 aminopeptidase and PDI, the former a recognised target of drug development, were both shown to have a micronemal location by IFA. We further identified numerous proteins with established vesicle trafficking and signaling functions consistent with micronemes being part of a regulated secretory pathway. Previously uncharacterised proteins comprise the largest functional group of the microneme proteome and will include secreted proteins important to invasion.
Kalpana Lal, Judith Prieto, Elizabeth Bromley, Sanya Sanderson, John Yates, Jonathan Wastling, Fiona Tomley, Robert Sinden
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Malaria research in the post-genomic era

CiteULike malaria tags - 19 September 2016 - 1:05pm
Nature, Vol. 455, No. 7214. (09 October 2008), pp. 751-756, doi:10.1038/nature07361

For many pathogens the availability of genome sequence, permitting genome-dependent methods of research, can partially substitute for powerful forward genetic methods (genome-independent) that have advanced model organism research for decades. In 2002 the genome sequence of Plasmodium falciparum, the parasite causing the most severe type of human malaria, was completed, eliminating many of the barriers to performing state-of-the-art molecular biological research on malaria parasites. Although new, licensed therapies may not yet have resulted from genome-dependent experiments, they have produced a wealth of new observations about the basic biology of malaria parasites, and it is likely that these will eventually lead to new therapeutic approaches. This review will focus on the basic research discoveries that have depended, in part, on the availability of the Plasmodium genome sequences.
Elizabeth Winzeler
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Proteomic Profiling of Plasmodium Sporozoite Maturation Identifies New Proteins Essential for Parasite Development and Infectivity

CiteULike malaria tags - 19 September 2016 - 12:47pm
PLoS Pathog, Vol. 4, No. 10. (31 October 2008), e1000195, doi:10.1371/journal.ppat.1000195

Plasmodium falciparum sporozoites that develop and mature inside an Anopheles mosquito initiate a malaria infection in humans. Here we report the first proteomic comparison of different parasite stages from the mosquito—early and late oocysts containing midgut sporozoites, and the mature, infectious salivary gland sporozoites. Despite the morphological similarity between midgut and salivary gland sporozoites, their proteomes are markedly different, in agreement with their increase in hepatocyte infectivity. The different sporozoite proteomes contain a large number of stage specific proteins whose annotation suggest an involvement in sporozoite maturation, motility, infection of the human host and associated metabolic adjustments. Analyses of proteins identified in the P. falciparum sporozoite proteomes by orthologous gene disruption in the rodent malaria parasite, P. berghei, revealed three previously uncharacterized Plasmodium proteins that appear to be essential for sporozoite development at distinct points of maturation in the mosquito. This study sheds light on the development and maturation of the malaria parasite in an Anopheles mosquito and also identifies proteins that may be essential for sporozoite infectivity to humans. Human malaria is caused by Plasmodium falciparum, a unicellular protozoan parasite that is transmitted by Anopheles mosquitoes. An infectious mosquito injects saliva containing sporozoite forms of the parasite and these then migrate from the skin to the liver, where they establish an infection. Many intervention strategies are currently focused on preventing the establishment of infection by sporozoites. Clearly, an understanding of the biology of the sporozoite is essential for developing new intervention strategies. Sporozoites are produced within the oocyst, located on the outside wall of the mosquito midgut, and migrate after release from the oocysts to the salivary glands where they are stored as mature infectious forms. Comparison of the proteomes of sporozoites derived from either the oocyst or from the salivary gland reveals remarkable differences in the protein content of these stages despite their similar morphology. The changes in protein content reflect the very specific preparations the sporozoites make in order to establish an infection of the liver. Analysis of the function of several previously uncharacterized, conserved proteins revealed proteins essential for sporozoite development at distinct points of their maturation.
Edwin Lasonder, Chris Janse, Geert-Jan van Gemert, Gunnar Mair, Adriaan Vermunt, Bruno Douradinha, Vera van Noort, Martijn Huynen, Adrian Luty, Hans Kroeze, Shahid Khan, Robert Sauerwein, Andrew Waters, Matthias Mann, Hendrik Stunnenberg
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The silent path to thousands of merozoites: the Plasmodium liver stage

CiteULike malaria tags - 19 September 2016 - 12:32pm
Nature Reviews Microbiology, Vol. 4, No. 11. (01 November 2006), pp. 849-856, doi:10.1038/nrmicro1529

Plasmodium sporozoites are deposited in the skin of their vertebrate hosts through the bite of an infected female Anopheles mosquito. Most of these parasites find a blood vessel and travel in the peripheral blood circulation until they reach the liver sinusoids. Once there, the sporozoites cross the sinusoidal wall and migrate through several hepatocytes before they infect a final hepatocyte, with the formation of a parasitophorous vacuole, in which the intrahepatic form of the parasite grows and multiplies. During this period, each sporozoite generates thousands of merozoites. As the development of Plasmodium sporozoites inside hepatocytes is an obligatory step before the onset of disease, understanding the parasite's requirements during this period is crucial for the development of any form of early intervention. This Review summarizes our current knowledge on this stage of the Plasmodium life cycle.
Miguel Prudencio, Ana Rodriguez, Maria Mota
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Invasion in vitro of mosquito midgut cells by the malaria parasite proceeds by a conserved mechanism and results in death of the invaded midgut cells

CiteULike malaria tags - 18 September 2016 - 6:23pm
Proceedings of the National Academy of Sciences, Vol. 97, No. 21. (10 October 2000), pp. 11516-11521, doi:10.1073/pnas.97.21.11516

Using an in vitro culture system, we observed the migration of malaria ookinetes on the surface of the mosquito midgut and invasion of the midgut epithelium. Ookinetes display constrictions during migration to the midgut surface and a gliding motion once on the luminal midgut surface. Invasion of a midgut cell always occurs at its lateral apical surface. Invasion is rapid and is often followed by invasion of a neighboring midgut cell by the ookinete. The morphology of the invaded cells changes dramatically after invasion, and invaded cells die rapidly. Midgut cell death is accompanied by activation of a caspase-3-like protease, suggesting cell death is apoptotic. The events occurring during invasion were identical for two different species of Plasmodium and two different genera of mosquitoes; they probably represent a universal mechanism of mosquito midgut penetration by the malaria parasite.
Helge Zieler, James Dvorak
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Role of host cell traversal by the malaria sporozoite during liver infection

CiteULike malaria tags - 17 September 2016 - 11:07pm
The Journal of Experimental Medicine, Vol. 210, No. 5. (06 May 2013), pp. 905-915, doi:10.1084/jem.20121130
Joana Tavares, Pauline Formaglio, Sabine Thiberge, Elodie Mordelet, Nico Van Rooijen, Alexander Medvinsky, Robert Ménard, Rogerio Amino
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A toolbox to study liver stage malaria

CiteULike malaria tags - 16 September 2016 - 8:32pm
Trends in Parasitology, Vol. 27, No. 12. (December 2011), pp. 565-574, doi:10.1016/

The first obligatory phase of mammalian infection by Plasmodium parasites, the causative agents of malaria, occurs in the liver of the host. This stage of Plasmodium infection bears enormous potential for anti-malarial intervention. Recent technological progress has strongly contributed to overcoming some of the long-standing difficulties in experimentally assessing hepatic infection by Plasmodium. Here, we review appropriate infection models and infection assessment tools, and provide a comprehensive description of recent advances in experimental strategies to investigate the liver stage of malaria. These issues are discussed in the context of current challenges in the field to provide researchers with the technical tools that enable effective experimental approaches to study liver stage malaria.
Miguel Prudêncio, Maria Mota, António Mendes
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The cellular and molecular basis for malaria parasite invasion of the human red blood cell

CiteULike malaria tags - 16 September 2016 - 8:07pm
The Journal of Cell Biology, Vol. 198, No. 6. (17 September 2012), pp. 961-971, doi:10.1083/jcb.201206112

Malaria is a major disease of humans caused by protozoan parasites from the genus Plasmodium. It has a complex life cycle; however, asexual parasite infection within the blood stream is responsible for all disease pathology. This stage is initiated when merozoites, the free invasive blood-stage form, invade circulating erythrocytes. Although invasion is rapid, it is the only time of the life cycle when the parasite is directly exposed to the host immune system. Significant effort has, therefore, focused on identifying the proteins involved and understanding the underlying mechanisms behind merozoite invasion into the protected niche inside the human erythrocyte.
Alan Cowman, Drew Berry, Jake Baum
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Host cell remodeling by pathogens: the exomembrane system in Plasmodium-infected erythrocytes

CiteULike malaria tags - 8 September 2016 - 12:47pm
FEMS Microbiology Reviews, Vol. 40, No. 5. (01 September 2016), pp. 701-721, doi:10.1093/femsre/fuw016
Emma Sherling, Christiaan van Ooij, Alain Filloux
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Indels, structural variation, and recombination drive genomic diversity in Plasmodium falciparum

CiteULike malaria tags - 18 August 2016 - 9:51am
Genome Research (16 August 2016), doi:10.1101/gr.203711.115

An international, peer-reviewed genome sciences journal featuring outstanding original research that offers novel insights into the biology of all organisms
Alistair Miles, Zamin Iqbal, Paul Vauterin, Richard Pearson, Susana Campino, Michel Theron, Kelda Gould, Daniel Mead, Eleanor Drury, John O'Brien, Valentin Rubio, Bronwyn MacInnis, Jonathan Mwangi, Upeka Samarakoon, Lisa Ranford-Cartwright, Michael Ferdig, Karen Hayton, Xin-zhuan Su, Thomas Wellems, Julian Rayner, Gil McVean, Dominic Kwiatkowski
Categories: malaria news feeds

Whole genome sequencing of Plasmodium falciparum from dried blood spots using selective whole genome amplification

CiteULike malaria tags - 12 August 2016 - 8:56am
bioRxiv (11 August 2016), 067546, doi:10.1101/067546

bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution
Samuel Oyola, Cristina Ariani, William Hamilton, Mihir Kekre, Lucas Amenga-Etego, Anita Ghansah, Gavin Rutledge, Seth Redmond, Magnus Manske, Dushyanth Jyothi, Chris Jacob, Thomas Otto, Kirk Rockett, Chris Newbold, Matthew Berriman, Dominic Kwiatkowski
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Estimating Geographical Variation in the Risk of Zoonotic Plasmodium knowlesi Infection in Countries Eliminating Malaria

CiteULike malaria tags - 11 August 2016 - 10:08am
PLoS Negl Trop Dis, Vol. 10, No. 8. (5 August 2016), e0004915, doi:10.1371/journal.pntd.0004915

Author Summary Plasmodium knowlesi is a malaria parasite found in wild monkey populations and transmitted from this animal reservoir to humans via infected mosquitoes. It causes severe and fatal disease in humans, and is the most common cause of malaria in parts of Malaysia. The geographical distribution of this disease is largely unknown because it is often misdiagnosed as one of the human malarias. Human malaria parasites are primarily transmitted between humans via mosquitoes and are not frequently transmitted from other animals to humans. Many countries in Southeast Asia, where P. knowlesi infections have been reported, are making progress towards eliminating the human malarias. Understanding the geographical distribution of P. knowlesi is important for identifying areas where malaria transmission will continue after the human malarias have been eliminated. In locations that have high volumes of P. knowlesi infection data, we modelled patterns of variation in the data linked to environmental predictors, and used this to estimate P. knowlesi infection risk in locations where data is lacking. The resulting map represents an initial evidence-base for identifying areas of human disease risk that should be prioritized for surveillance, particularly in the context of malaria elimination in the region.
Freya Shearer, Zhi Huang, Daniel Weiss, Antoinette Wiebe, Harry Gibson, Katherine Battle, David Pigott, Oliver Brady, Chaturong Putaporntip, Somchai Jongwutiwes, Yee Lau, Magnus Manske, Roberto Amato, Iqbal Elyazar, Indra Vythilingam, Samir Bhatt, Peter Gething, Balbir Singh, Nick Golding, Simon Hay, Catherine Moyes
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Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond

CiteULike malaria tags - 4 August 2016 - 9:49am
PLoS Pathog, Vol. 12, No. 7. (28 July 2016), e1005763, doi:10.1371/journal.ppat.1005763

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts. Malaria leads to the loss of over 440,000 lives annually; accelerating research to discover new candidate drugs is a priority. Medicines for Malaria Venture (MMV) has distilled over 25,000 compounds that kill malaria parasites in vitro into a group of 400 representative compounds, called the "Malaria Box". These Malaria Box sets were distributed free-of-charge to research laboratories in 30 different countries that work on a wide variety of pathogens. Fifty-five groups compiled >290 assay results for this paper describing the many activities of the Malaria Box compounds. The collective results suggest a potential mechanism of action for over 130 compounds against malaria and illuminate the most promising compounds for further malaria drug development research. Excitingly some of these compounds also showed outstanding activity against other disease agents including fungi, bacteria, other single-cellular parasites, worms, and even human cancer cells. The results have ignited over 30 drug development programs for a variety of diseases. This open access effort was so successful that MMV has begun to distribute another set of compounds with initial activity against a wider range of infectious agents that are of public health concern, called the Pathogen Box, available now to scientific labs all over the world (
Wesley Van Voorhis, John Adams, Roberto Adelfio, Vida Ahyong, Myles Akabas, Pietro Alano, Aintzane Alday, Yesmalie Alemán Resto, Aishah Alsibaee, Ainhoa Alzualde, Katherine Andrews, Simon Avery, Vicky Avery, Lawrence Ayong, Mark Baker, Stephen Baker, Choukri Ben Mamoun, Sangeeta Bhatia, Quentin Bickle, Lotfi Bounaadja, Tana Bowling, Jürgen Bosch, Lauren Boucher, Fabrice Boyom, Jose Brea, Marian Brennan, Audrey Burton, Conor Caffrey, Grazia Camarda, Manuela Carrasquilla, Dee Carter, Maria Belen Cassera, Ken Chih-Chien Cheng, Worathad Chindaudomsate, Anthony Chubb, Beatrice Colon, Daisy Colón-López, Yolanda Corbett, Gregory Crowther, Noemi Cowan, Sarah D'Alessandro, Na Le Dang, Michael Delves, Joseph DeRisi, Alan Du, Sandra Duffy, Shimaa Abd El-Salam El-Sayed, Michael Ferdig, José Fernández Robledo, David Fidock, Isabelle Florent, Patrick Fokou, Ani Galstian, Francisco Gamo, Suzanne Gokool, Ben Gold, Todd Golub, Gregory Goldgof, Rajarshi Guha, Armand Guiguemde, Nil Gural, Kiplin Guy, Michael Hansen, Kirsten Hanson, Andrew Hemphill, Rob Hooft van Huijsduijnen, Takaaki Horii, Paul Horrocks, Tyler Hughes, Christopher Huston, Ikuo Igarashi, Katrin Ingram-Sieber, Maurice Itoe, Ajit Jadhav, Amornrat Naranuntarat Jensen, Laran Jensen, Rays Jiang, Annette Kaiser, Jennifer Keiser, Thomas Ketas, Sebastien Kicka, Sunyoung Kim, Kiaran Kirk, Vidya Kumar, Dennis Kyle, Maria Lafuente, Scott Landfear, Nathan Lee, Sukjun Lee, Adele Lehane, Fengwu Li, David Little, Liqiong Liu, Manuel Llinás, Maria Loza, Aristea Lubar, Leonardo Lucantoni, Isabelle Lucet, Louis Maes, Dalu Mancama, Nuha Mansour, Sandra March, Sheena McGowan, Iset Medina Vera, Stephan Meister, Luke Mercer, Jordi Mestres, Alvine Mfopa, Raj Misra, Seunghyun Moon, John Moore, Francielly Morais Rodrigues da Costa, Joachim Müller, Arantza Muriana, Stephen Nakazawa Hewitt, Bakela Nare, Carl Nathan, Nathalie Narraidoo, Sujeevi Nawaratna, Kayode Ojo, Diana Ortiz, Gordana Panic, George Papadatos, Silvia Parapini, Kailash Patra, Ngoc Pham, Sarah Prats, David Plouffe, Sally-Ann Poulsen, Anupam Pradhan, Celia Quevedo, Ronald Quinn, Christopher Rice, Mohamed Abdo Rizk, Andrea Ruecker, Robert St. Onge, Rafaela Salgado Ferreira, Jasmeet Samra, Natalie Robinett, Ulrich Schlecht, Marjorie Schmitt, Filipe Silva Villela, Francesco Silvestrini, Robert Sinden, Dennis Smith, Thierry Soldati, Andreas Spitzmüller, Serge Stamm, David Sullivan, William Sullivan, Sundari Suresh, Brian Suzuki, Yo Suzuki, Joshua Swamidass, Donatella Taramelli, Lauve Tchokouaha, Anjo Theron, David Thomas, Kathryn Tonissen, Simon Townson, Abhai Tripathi, Valentin Trofimov, Kenneth Udenze, Imran Ullah, Cindy Vallieres, Edgar Vigil, Joseph Vinetz, Phat Voong Vinh, Hoan Vu, Nao-aki Watanabe, Kate Weatherby, Pamela White, Andrew Wilks, Elizabeth Winzeler, Edward Wojcik, Melanie Wree, Wesley Wu, Naoaki Yokoyama, Paul Zollo, Nada Abla, Benjamin Blasco, Jeremy Burrows, Benoît Laleu, Didier Leroy, Thomas Spangenberg, Timothy Wells, Paul Willis
Categories: malaria news feeds

Diverse chemotypes disrupt ion homeostasis in the malaria parasite

CiteULike malaria tags - 2 August 2016 - 10:43am
Molecular Microbiology, Vol. 94, No. 2. (1 October 2014), pp. 327-339, doi:10.1111/mmi.12765

The antimalarial spiroindolones disrupt Plasmodium falciparum Na+ regulation and induce an alkalinization of the parasite cytosol. It has been proposed that they do so by inhibiting PfATP4, a parasite plasma membrane P-type ATPase postulated to export Na+ and import H+ equivalents. Here, we screened the 400 antiplasmodial compounds of the open access ‘Malaria Box’ for their effects on parasite ion regulation. Twenty eight compounds affected parasite Na+ and pH regulation in a manner consistent with PfATP4 inhibition. Six of these, with chemically diverse structures, were selected for further analysis. All six showed reduced antiplasmodial activity against spiroindolone-resistant parasites carrying mutations in pfatp4. We exposed parasites to incrementally increasing concentrations of two of the six compounds and in both cases obtained resistant parasites with mutations in pfatp4. The finding that diverse chemotypes have an apparently similar mechanism of action indicates that PfATP4 may be a significant Achilles' heel for the parasite.
Adele Lehane, Melanie Ridgway, Eileen Baker, Kiaran Kirk
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Genomic analysis reveals a common breakpoint in amplifications of the Plasmodium vivax multidrug resistance 1 locus in Thailand

CiteULike malaria tags - 28 July 2016 - 9:46am
Journal of Infectious Diseases (24 July 2016), jiw323, doi:10.1093/infdis/jiw323

In co-endemic regions where mefloquine is used to treat Plasmodium falciparum, drug pressure may select for mefloquine-resistant P. vivax mediated by increased copy number of the multidrug resistance 1 gene (pvmdr1). Surveillance is not undertaken routinely owing in part to methodological challenges in detection of gene amplification. Using genomic data on 88 P. vivax samples from western Thailand, we identified pvmdr1 amplification in 17 isolates, all exhibiting tandem copies of a 37.6 Kb region with identical breakpoints. A novel breakpoint-specific PCR assay was designed to detect the amplification. The assay demonstrated high sensitivity, identifying amplifications in 13 additional, polyclonal infections. Application to 132 further samples identified the common breakpoint in all years tested (2003-2015), with decline in prevalence after 2012 corresponding with local discontinuation of mefloquine regimens. Assessment of the structure of pvmdr1 amplification in other geographic regions will inform on the population-specificity of the breakpoints and underlying amplification mechanisms.
Sarah Auburn, David Serre, Richard Pearson, Roberto Amato, Kanlaya Sriprawat, Sheren To, Irene Handayuni, Rossarin Suwanarusk, Bruce Russell, Eleanor Drury, Jim Stalker, Olivo Miotto, Dominic Kwiatkowski, Francois Nosten, Ric Price
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Invasion of hepatocytes by Plasmodium sporozoites requires cGMP-dependent protein kinase and calcium dependent protein kinase 4

CiteULike malaria tags - 21 July 2016 - 10:08am
Molecular Microbiology (1 July 2016), pp. n/a-n/a, doi:10.1111/mmi.13466

Invasion of hepatocytes by sporozoites is essential for Plasmodium to initiate infection of the mammalian host. The parasite's subsequent intracellular differentiation in the liver is the first developmental step of its mammalian cycle. Despite their biological significance, surprisingly little is known of the signaling pathways required for sporozoite invasion. We report that sporozoite invasion of hepatocytes requires signaling through two second-messengers - cGMP mediated by the parasite's cGMP-dependent protein kinase (PKG), and Ca2+, mediated by the parasite's calcium-dependent protein kinase 4 (CDPK4). Sporozoites expressing a mutated form of P. berghei PKG or carrying a deletion of the CDPK4 gene were defective in invasion of hepatocytes. Using specific and potent inhibitors of Plasmodium PKG and CDPK4, we demonstrated that PKG and CDPK4 are required for sporozoite motility, and that PKG regulates the secretion of TRAP, an adhesin that is essential for motility. Chemical inhibition of PKG decreased parasite egress from hepatocytes by inhibiting either the formation or release of merosomes. In contrast, genetic inhibition of CDPK4 does not significantly decrease the number of merosomes. By revealing the requirement for PKG and CDPK4 in Plasmodium sporozoite invasion, our work enables a better understanding of kinase pathways that act in different Plasmodium stages. This article is protected by copyright. All rights reserved.
K Govindasamy, S Jebiwott, DK Jaijyan, A Davidow, KK Ojo, WC Van Voorhis, M Brochet, O Billker, P Bhanot
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Unravelling the Laverania

CiteULike malaria tags - 15 July 2016 - 8:34am
Nat Rev Micro, Vol. 14, No. 8. (August 2016), pp. 478-478, doi:10.1038/nrmicro.2016.109
William Proto
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