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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
Categories: malaria news feeds

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
Categories: malaria news feeds

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
Categories: malaria news feeds

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
Categories: malaria news feeds

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
Categories: malaria news feeds

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
Categories: malaria news feeds

Binding of Plasmodium falciparum Merozoite Surface Proteins DBLMSP and DBLMSP2 to Human Immunoglobulin M Is Conserved among Broadly Diverged Sequence Variants

CiteULike malaria tags - 14 July 2016 - 11:08am
Journal of Biological Chemistry, Vol. 291, No. 27. (01 July 2016), pp. 14285-14299, doi:10.1074/jbc.m116.722074

Diversity at pathogen genetic loci can be driven by host adaptive immune selection pressure and may reveal proteins important for parasite biology. Population-based genome sequencing of Plasmodium falciparum, the parasite responsible for the most severe form of malaria, has highlighted two related polymorphic genes called dblmsp and dblmsp2, which encode Duffy binding-like (DBL) domain-containing proteins located on the merozoite surface but whose function remains unknown. Using recombinant proteins and transgenic parasites, we show that DBLMSP and DBLMSP2 directly and avidly bind human IgM via their DBL domains. We used whole genome sequence data from over 400 African and Asian P. falciparum isolates to show that dblmsp and dblmsp2 exhibit extreme protein polymorphism in their DBL domain, with multiple variants of two major allelic classes present in every population tested. Despite this variability, the IgM binding function was retained across diverse sequence representatives. Although this interaction did not seem to have an effect on the ability of the parasite to invade red blood cells, binding of DBLMSP and DBLMSP2 to IgM inhibited the overall immunoreactivity of these proteins to IgG from patients who had been exposed to the parasite. This suggests that IgM binding might mask these proteins from the host humoral immune system.
Cécile Crosnier, Zamin Iqbal, Ellen Knuepfer, Sorina Maciuca, Abigail Perrin, Gathoni Kamuyu, David Goulding, Leyla Bustamante, Alistair Miles, Shona Moore, Gordon Dougan, Anthony Holder, Dominic Kwiatkowski, Julian Rayner, Richard Pleass, Gavin Wright
Categories: malaria news feeds

A Stem Cell Strategy Identifies Glycophorin C as a Major Erythrocyte Receptor for the Rodent Malaria Parasite Plasmodium berghei

CiteULike malaria tags - 8 July 2016 - 8:16am
PLoS ONE, Vol. 11, No. 6. (30 June 2016), e0158238, doi:10.1371/journal.pone.0158238

The clinical complications of malaria are caused by the parasite expansion in the blood. Invasion of erythrocytes is a complex process that depends on multiple receptor-ligand interactions. Identification of host receptors is paramount for fighting the disease as it could reveal new intervention targets, but the enucleated nature of erythrocytes makes genetic approaches impossible and many receptors remain unknown. Host-parasite interactions evolve rapidly and are therefore likely to be species-specific. As a results, understanding of invasion receptors outside the major human pathogen Plasmodium falciparum is very limited. Here we use mouse embryonic stem cells (mESCs) that can be genetically engineered and differentiated into erythrocytes to identify receptors for the rodent malaria parasite Plasmodium berghei. Two proteins previously implicated in human malaria infection: glycophorin C (GYPC) and Band-3 (Slc4a1) were deleted in mESCs to generate stable cell lines, which were differentiated towards erythropoiesis. In vitro infection assays revealed that while deletion of Band-3 has no effect, absence of GYPC results in a dramatic decrease in invasion, demonstrating the crucial role of this protein for P. berghei infection. This stem cell approach offers the possibility of targeting genes that may be essential and therefore difficult to disrupt in whole organisms and has the potential to be applied to a variety of parasites in diverse host cell types.
Loukia Yiangou, Ruddy Montandon, Katarzyna Modrzynska, Barry Rosen, Wendy Bushell, Christine Hale, Oliver Billker, Julian Rayner, Alena Pance
Categories: malaria news feeds

The structure of sperm Izumo1 reveals unexpected similarities with Plasmodium invasion proteins

CiteULike malaria tags - 8 July 2016 - 7:57am
Current Biology (June 2016), doi:10.1016/j.cub.2016.06.028

Fertilization, the culminating event in sexual reproduction, occurs when haploid sperm and egg recognize each other and fuse to form a diploid zygote. In mammals this process critically depends on the interaction between Izumo1, a protein exposed on the equatorial segment of acrosome-reacted sperm, and the egg plasma-membrane-anchored receptor Juno 1 and 2. The molecular mechanism triggering gamete fusion is unresolved because both Izumo1 and Juno lack sequence similarity to known membrane fusogens. Here we report the crystal structure of Izumo1, which reveals a membrane distal region composed of a four-helix bundle connected to a carboxy-terminal immunoglobulin (Ig)-like domain through a β-hairpin stabilized by disulfide bonds. Remarkably, different regions of Izumo1 display significant structural similarities to two proteins expressed by the invasive sporozoite stage of Plasmodium parasites: SPECT1, which is essential for host cell traversal and hepatocyte invasion [3]; and TRAP, which is necessary for gliding motility and invasion [4]. These observations suggest a link between the molecular mechanisms underlying host cell invasion by the malaria parasite and gamete membrane fusion at fertilization.
Kaoru Nishimura, Ling Han, Enrica Bianchi, Gavin Wright, Daniele de Sanctis, Luca Jovine
Categories: malaria news feeds

Genomic analysis of local variation and recent evolution in Plasmodium vivax

CiteULike malaria tags - 1 July 2016 - 8:12am
Nat Genet, Vol. advance online publication (27 June 2016), doi:10.1038/ng.3599
Richard Pearson, Roberto Amato, Sarah Auburn, Olivo Miotto, Jacob Almagro-Garcia, Chanaki Amaratunga, Seila Suon, Sivanna Mao, Rintis Noviyanti, Hidayat Trimarsanto, Jutta Marfurt, Nicholas Anstey, Timothy William, Maciej Boni, Christiane Dolecek, Hien Tran, Nicholas White, Pascal Michon, Peter Siba, Livingstone Tavul, Gabrielle Harrison, Alyssa Barry, Ivo Mueller, Marcelo Ferreira, Nadira Karunaweera, Milijaona Randrianarivelojosia, Qi Gao, Christina Hubbart, Lee Hart, Ben Jeffery, Eleanor Drury, Daniel Mead, Mihir Kekre, Susana Campino, Magnus Manske, Victoria Cornelius, Bronwyn MacInnis, Kirk Rockett, Alistair Miles, Julian Rayner, Rick Fairhurst, Francois Nosten, Ric Price, Dominic Kwiatkowski
Categories: malaria news feeds

A Novel Way to Grow Hemozoin-Like Crystals In Vitro and Its Use to Screen for Hemozoin Inhibiting Antimalarial Compounds

CiteULike malaria tags - 30 June 2016 - 10:59am
PLoS ONE, Vol. 7, No. 7. (18 July 2012), e41006, doi:10.1371/journal.pone.0041006

Hemozoin crystals are normally formed in vivo by Plasmodium parasites to detoxify free heme released after hemoglobin digestion during its intraerythrocytic stage. Inhibition of hemozoin formation by various drugs results in free heme concentration toxic for the parasites. As a consequence, in vitro assays have been developed to screen and select candidate antimalarial drugs based on their capacity to inhibit hemozoin formation. In this report we describe new ways to form hemozoin-like crystals that were incidentally discovered during research in the field of prion inactivation. We investigated the use of a new assay based on naturally occurring “self-replicating” particles and previously described as presenting resistance to decontamination comparable to prions. The nature of these particles was determined using electron microscopy, Maldi-Tof analysis and X-ray diffraction. They were compared to synthetic hemozoin and to hemozoin obtained from Plasmodium falciparum. We then used the assay to evaluate the capacity of various antimalarial and anti-prion compounds to inhibit “self-replication” (crystallisation) of these particles. We identified these particles as being similar to ferriprotoporphyrin IX crystal and confirmed the ability of these particles to serve as nuclei for growth of new hemozoin-like crystals (HLC). HLC are morphologically similar to natural and synthetic hemozoin. Growth of HLC in a simple assay format confirmed inhibition by quinolines antimalarials at potencies described in the literature. Interestingly, artemisinins and tetracyclines also seemed to inhibit HLC growth. The described HLC assay is simple and easy to perform and may have the potential to be used as an additional tool to screen antimalarial drugs for their hemozoin inhibiting activity. As already described by others, drugs that inhibit hemozoin crystal formation have also the potential to inhibit misfolded proteins assemblies formation.
Vincent Thomas, Ana Góis, Bruce Ritts, Peter Burke, Thomas Hänscheid, Gerald McDonnell
Categories: malaria news feeds

Targeting the Lipid Metabolic Pathways for the Treatment of Malaria.

CiteULike malaria tags - 17 June 2016 - 11:09am
Drug development research, Vol. 71, No. 1. (February 2010), pp. 44-55, doi:10.1002/ddr.20347

The control and eventual eradication of human malaria is considered one of the most important global public health goals of the 21st Century. Malaria, caused by intraerythrocytic protozoan parasites of the genus Plasmodium, is by far the most lethal and among the most prevalent of the infectious diseases. Four species of Plasmodium (P. falciparum, P. malariae, P. ovale, and P. vivax) are known to be infectious to humans, and more recent cases of infection due to P. knowlesi also have been reported. These species cause approximately 300 million annual cases of clinical malaria resulting in around one million deaths mostly caused by P. falciparum. The rapid emergence of drug-resistant Plasmodium strains has severely reduced the potency of medicines commonly used to treat and block the transmission of malaria and threatens the effectiveness of combination therapy in the field. New drugs that target important parasite functions, which are not the target of current antimalarial drugs, and have the potential to act against multi-drug-resistant Plasmodium strains are urgently needed. Recent studies in P. falciparum have unraveled new metabolic pathways for the synthesis of the parasite phospholipids and fatty acids. The present review summarizes our current understanding of these pathways in Plasmodium development and pathogenesis, and provides an update on the efforts underway to characterize their importance using genetic means and to develop antimalarial therapies targeting lipid metabolic pathways.
Choukri Ben Mamoun, Sean Prigge, Henri Vial
Categories: malaria news feeds

Multigenomic Delineation of Plasmodium Species of the Laverania Subgenus Infecting Wild-living Chimpanzees and Gorillas

CiteULike malaria tags - 16 June 2016 - 9:56am
Genome Biology and Evolution (11 June 2016), evw128, doi:10.1093/gbe/evw128

Plasmodium falciparum, the major cause of malaria morbidity and mortality worldwide, is only distantly related to other human malaria parasites, and has thus been placed in a separate subgenus, termed Laverania. Parasites morphologically similar to P. falciparum have been identified in African apes, but only one other Laverania species, P. reichenowi from chimpanzees, has been formally described. Although recent studies have pointed to the existence of additional Laverania species, their precise number and host associations remain uncertain, primarily because of limited sampling and a paucity of parasite sequences other than from mitochondrial DNA. To address this, we used limiting dilution PCR to amplify additional parasite sequences from a large number of chimpanzee and gorilla blood and fecal samples collected at two sanctuaries and 30 field sites across equatorial Africa. Phylogenetic analyses of more than 2,000 new sequences derived from the mitochondrial, nuclear and apicoplast genomes revealed six divergent and well-supported clades within the Laverania parasite group. Although two of these clades exhibited deep subdivisions in phylogenies estimated from organelle gene sequences, these sublineages were geographically defined and not present in trees from four unlinked nuclear loci. This greatly expanded sequence data set thus confirms six, and not seven or more, ape Laverania species, of which P. reichenowi, P. gaboni, and P. billcollinsi only infect chimpanzees, while P. praefalciparum, P. adleri, P. blacklocki only infect gorillas. The new sequence data also confirm the P. praefalciparum origin of human P. falciparum.
Weimin Liu, Sesh Sundararaman, Dorothy Loy, Gerald Learn, Yingying Li, Lindsey Plenderleith, Jean-Bosco Ndjango, Sheri Speede, Rebeca Atencia, Debby Cox, George Shaw, Ahidjo Ayouba, Martine Peeters, Julian Rayner, Beatrice Hahn, Paul Sharp
Categories: malaria news feeds

Microsatellite genotyping and genome-wide single nucleotide polymorphism-based indices of Plasmodium falciparum diversity within clinical infections

CiteULike malaria tags - 19 May 2016 - 4:23pm
Malaria Journal, Vol. 15, No. 1. (12 May 2016), doi:10.1186/s12936-016-1324-4
Lee Murray, Victor Mobegi, Craig Duffy, Samuel Assefa, Dominic Kwiatkowski, Eugene Laman, Kovana Loua, David Conway
Categories: malaria news feeds

Role of Plasmodium vivax Duffy-binding protein 1 in invasion of Duffy-null Africans

CiteULike malaria tags - 19 May 2016 - 3:35pm
Proceedings of the National Academy of Sciences (17 May 2016), 201606113, doi:10.1073/pnas.1606113113
Karthigayan Gunalan, Eugenia Lo, Jessica Hostetler, Delenasaw Yewhalaw, Jianbing Mu, Daniel Neafsey, Guiyun Yan, Louis Miller
Categories: malaria news feeds

An Antibody Screen of a Plasmodium vivax Antigen Library Identifies Novel Merozoite Proteins Associated with Clinical Protection

CiteULike malaria tags - 19 May 2016 - 3:08pm
PLOS Neglected Tropical Diseases, Vol. 10, No. 5. (16 May 2016), e0004639, doi:10.1371/journal.pntd.0004639
Camila França, Jessica Hostetler, Sumana Sharma, Michael White, Enmoore Lin, Benson Kiniboro, Andreea Waltmann, Andrew Darcy, Connie Li Wai Suen, Peter Siba, Christopher King, Julian Rayner, Rick Fairhurst, Ivo Mueller
Categories: malaria news feeds

Genomic epidemiology of artemisinin resistant malaria

CiteULike malaria tags - 16 May 2016 - 6:55pm
eLife, Vol. 5 (04 March 2016), e08714, doi:10.7554/elife.08714

Genomic epidemiology of artemisinin resistant malaria | Plasmodium falciparum kelch13 mutations that cause artemisinin resistant malaria in Southeast Asia show markedly different patterns of evolutionary selection in Africa.
Categories: malaria news feeds

Combinatorial Genetic Modeling of pfcrt-Mediated Drug Resistance Evolution in Plasmodium falciparum

CiteULike malaria tags - 16 May 2016 - 5:40pm
Molecular Biology and Evolution, Vol. 33, No. 6. (1 June 2016), pp. 1554-1570, doi:10.1093/molbev/msw037

The emergence of drug resistance continuously threatens global control of infectious diseases, including malaria caused by the protozoan parasite Plasmodium falciparum. A critical parasite determinant is the P. falciparum chloroquine resistance transporter (PfCRT), the primary mediator of chloroquine (CQ) resistance (CQR), and a pleiotropic modulator of susceptibility to several first-line artemisinin-based combination therapy partner drugs. Aside from the validated CQR molecular marker K76T, P. falciparum parasites have acquired at least three additional pfcrt mutations, whose contributions to resistance and fitness have been heretofore unclear. Focusing on the quadruple-mutant Ecuadorian PfCRT haplotype Ecu1110 (K76T/A220S/N326D/I356L), we genetically modified the pfcrt locus of isogenic, asexual blood stage P. falciparum parasites using zinc-finger nucleases, producing all possible combinations of intermediate pfcrt alleles. Our analysis included the related quintuple-mutant PfCRT haplotype 7G8 (Ecu1110 + C72S) that is widespread throughout South America and the Western Pacific. Drug susceptibilities and in vitro growth profiles of our combinatorial pfcrt-modified parasites were used to simulate the mutational trajectories accessible to parasites as they evolved CQR. Our results uncover unique contributions to parasite drug resistance and growth for mutations beyond K76T and predict critical roles for the CQ metabolite monodesethyl-CQ and the related quinoline-type drug amodiaquine in driving mutant pfcrt evolution. Modeling outputs further highlight the influence of parasite proliferation rates alongside gains in drug resistance in dictating successful trajectories. Our findings suggest that P. falciparum parasites have navigated constrained pfcrt adaptive landscapes by means of probabilistically rare mutational bursts that led to the infrequent emergence of pfcrt alleles in the field.
Stanislaw Gabryszewski, Charin Modchang, Lise Musset, Thanat Chookajorn, David Fidock
Categories: malaria news feeds