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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

Elusive Plasmodium Species Complete the Human Malaria Genome Set

CiteULike malaria tags - 13 May 2016 - 8:18am
bioRxiv (12 May 2016), 052696, doi:10.1101/052696

bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution
Gavin Rutledge, Ulrike Boehme, Mandy Sanders, Adam Reid, Oumou Maiga-Ascofare, Abdoulaye Djimde, Tobias Apinjoh, Lucas Amenga-Etego, Magnus Manske, John Barnwell, Francois Renaud, Benjamin Ollomo, Franck Prugnolle, Nicholas Anstey, Sarah Auburn, Ric Price, James McCarthy, Dominic Kwiatkowski, Chris Newbold, Matthew Berriman, Thomas Otto
Categories: malaria news feeds

CRISPR-Cas9-modified pfmdr1 protects Plasmodium falciparum asexual blood stages and gametocytes against a class of piperazine-containing compounds but potentiates artemisinin-based combination therapy partner drugs

CiteULike malaria tags - 9 May 2016 - 10:56am
Molecular Microbiology (1 May 2016), pp. n/a-n/a, doi:10.1111/mmi.13397

Emerging resistance to first-line antimalarial combination therapies threatens malaria treatment and the global elimination campaign. Improved therapeutic strategies are required to protect existing drugs and enhance treatment efficacy. We report that the piperazine-containing compound ACT-451840 exhibits single-digit nanomolar inhibition of the Plasmodium falciparum asexual blood stages and transmissible gametocyte forms. Genome sequence analyses of in vitro-derived ACT-451840-resistant parasites revealed single nucleotide polymorphisms in pfmdr1, which encodes a digestive vacuole membrane-bound ATP-binding cassette transporter known to alter P. falciparum susceptibility to multiple first-line antimalarials. CRISPR-Cas9 based gene editing confirmed that PfMDR1 point mutations mediated ACT-451840 resistance. Resistant parasites demonstrated increased susceptibility to the clinical drugs lumefantrine, mefloquine, quinine and amodiaquine. Stage V gametocytes harboring Cas9-introduced pfmdr1 mutations also acquired ACT-451840 resistance. These findings reveal that PfMDR1 mutations can impart resistance to compounds active against asexual blood stages and mature gametocytes. Exploiting PfMDR1 resistance mechanisms provides new opportunities for developing disease-relieving and transmission-blocking antimalarials.
Caroline Ng, Giulia Siciliano, Marcus Lee, Mariana de Almeida, Victoria Corey, Selina Bopp, Lucia Bertuccini, Sergio Wittlin, Rachel Kasdin, Amélie Le Bihan, Martine Clozel, Elizabeth Winzeler, Pietro Alano, David Fidock
Categories: malaria news feeds

Quantifying the Impact of Human Mobility on Malaria

CiteULike malaria tags - 29 April 2016 - 12:15pm
Science, Vol. 338, No. 6104. (11 October 2012), pp. 267-270, doi:10.1126/science.1223467

Human movements contribute to the transmission of malaria on spatial scales that exceed the limits of mosquito dispersal. Identifying the sources and sinks of imported infections due to human travel and locating high-risk sites of parasite importation could greatly improve malaria control programs. Here, we use spatially explicit mobile phone data and malaria prevalence information from Kenya to identify the dynamics of human carriers that drive parasite importation between regions. Our analysis identifies importation routes that contribute to malaria epidemiology on regional spatial scales.
A Wesolowski, N Eagle, AJ Tatem, DL Smith, AM Noor, RW Snow, CO Buckee
Categories: malaria news feeds

Genomic variation in two gametocyte non-producing Plasmodium falciparum clonal lines

CiteULike malaria tags - 28 April 2016 - 9:21am
Malaria Journal, Vol. 15, No. 1. (21 April 2016), doi:10.1186/s12936-016-1254-1
Susana Campino, Ernest Benavente, Samuel Assefa, Eloise Thompson, Laura Drought, Catherine Taylor, Zaria Gorvett, Celine Carret, Christian Flueck, Al Ivens, Dominic Kwiatkowski, Pietro Alano, David Baker, Taane Clark
Categories: malaria news feeds

Palmitoyl Transferases have Critical Roles in the Development of Mosquito and Liver Stages of Plasmodium

CiteULike malaria tags - 21 April 2016 - 11:50am
Cellular Microbiology (1 April 2016), pp. n/a-n/a, doi:10.1111/cmi.12601

As the Plasmodium parasite transitions between mammalian and mosquito host, it has to adjust quickly to new environments. Palmitoylation, a reversible and dynamic lipid posttranslational modification plays a central role in regulating this process and has been implicated with functions for parasite morphology, motility and host cell invasion. While proteins associated with the gliding motility machinery have been described to be palmitoylated, no palmitoyl transferase responsible for regulating gliding motility has previously been identified. Here, we characterize two palmityol transferases with gene tagging and gene deletion approaches. We identify DHHC3, a palmitoyl transferase as a mediator of ookinete development, with a crucial role for gliding motility in ookinetes and sporozoites and we co-localize the protein with a marker for the inner membrane complex in the ookinete stage. Ookinetes and sporozoites lacking DHHC3 are impaired in gliding motility and exhibit a strong phenotype in vivo; with ookinetes being significantly less infectious to their mosquito host and sporozoites being non-infectious to mice. Importantly, genetic complementation of the DHHC3-ko parasite completely restored virulence. We generated parasites lacking both DHHC3, as well as the palmitoyl transferase DHHC9, and found an enhanced phenotype for these double knockout parasites, allowing insights into the functional overlap and compensational nature of the large family of PbDHHCs. These findings contribute to our understanding of the organization and mechanism of the gliding motility machinery, which as is becoming increasingly clear, is mediated by palmitoylation. This article is protected by copyright. All rights reserved.
CS Hopp, AE Balaban, E Bushell, O Billker, JC Rayner, P Sinnis
Categories: malaria news feeds

Parasites resistant to the antimalarial atovaquone fail to transmit by mosquitoes

CiteULike malaria tags - 15 April 2016 - 8:59am
Science, Vol. 352, No. 6283. (14 April 2016), pp. 349-353, doi:10.1126/science.aad9279
CD Goodman, JE Siregar, V Mollard, J Vega-Rodriguez, D Syafruddin, H Matsuoka, M Matsuzaki, T Toyama, A Sturm, A Cozijnsen, M Jacobs-Lorena, K Kita, S Marzuki, GI McFadden
Categories: malaria news feeds

Study of Plasmodium falciparum DHHC palmitoyl-transferases identifies a role for PfDHHC9 in gametocytogenesis

CiteULike malaria tags - 13 April 2016 - 10:44am
Cellular Microbiology (1 April 2016), pp. n/a-n/a, doi:10.1111/cmi.12599

Palmitoylation is the post-translational reversible addition of the acyl moiety, palmitate, to cysteine residues of proteins, and is involved in regulating protein trafficking, localisation, stability and function. The DHHC protein family, named for their highly conserved Aspartate-Histidine-Histidine-Cysteine (DHHC) signature motif, is thought to be responsible for catalysing protein palmitoylation. Palmitoylation is widespread in all eukaryotes, including the malaria parasite, Plasmodium falciparum, where over 400 palmitoylated proteins are present in the asexual intraerythrocytic schizont stage parasites, including proteins involved in key aspects of parasite maturation and development. The P. falciparum genome includes 12 proteins containing the conserved DHHC motif. In this study, we adapted a palmitoyl-transferase activity assay for use with P. falciparum proteins and demonstrated for the first time that P. falciparum DHHC proteins are responsible for the palmitoylation of P. falciparum substrates. This assay also reveals that multiple DHHCs are capable of palmitoylating the same substrate, indicating functional redundancy at least in vitro. To test whether functional redundancy also exists in vivo, we investigated the endogenous localisation and essentiality of a subset of schizont-expressed PfDHHC proteins. Individual PfDHHC proteins localised to distinct organelles, including parasite-specific organelles such as the rhoptries and inner membrane complex. Knock-out studies identified individual DHHCs that may be essential for blood stage growth, and others that were functionally redundant in the blood stages but may have functions in other stages of parasite development. Supporting this hypothesis, disruption of PfDHHC9 had no effect on blood-stage growth, but reduced the formation of gametocytes, suggesting that this protein could be exploited as a transmission-blocking target. The localisation and stage-specific expression of the DHHC proteins may be important for regulating their substrate specificity and thus may provide a path for inhibitor development. This article is protected by copyright. All rights reserved.
Chwen Tay, Matthew Jones, Nicola Hodson, Michel Theron, Jyoti Choudhary, Julian Rayner
Categories: malaria news feeds

Genomic epidemiology of artemisinin resistant malaria

CiteULike malaria tags - 13 April 2016 - 9:58am
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.
MalariaGEN Plasmodium falciparum Community Project, Richard Neher, Roberto Amato, Olivo Miotto, Charles Woodrow, Jacob Almagro-Garcia, Ipsita Sinha, Susana Campino, Daniel Mead, Eleanor Drury, Mihir Kekre, Mandy Sanders, Alfred Amambua-Ngwa, Chanaki Amaratunga, Lucas Amenga-Etego, Voahangy Andrianaranjaka, Tobias Apinjoh, Elizabeth Ashley, Sarah Auburn, Gordon Awandare, Vito Baraka, Alyssa Barry, Maciej Boni, Steffen Borrmann, Teun Bousema, Oralee Branch, Peter Bull, Kesinee Chotivanich, David Conway, Alister Craig, Nicholas Day, Abdoulaye Djimdé, Christiane Dolecek, Arjen Dondorp, Chris Drakeley, Patrick Duffy, Diego Echeverry, Thomas Egwang, Rick Fairhurst, Md, Caterina Fanello, Tran Hien, Abraham Hodgson, Mallika Imwong, Deus Ishengoma, Pharath Lim, Chanthap Lon, Jutta Marfurt, Kevin Marsh, Mayfong Mayxay, Pascal Michon, Victor Mobegi, Olugbenga Mokuolu, Jacqui Montgomery, Ivo Mueller, Myat Kyaw, Paul Newton, Francois Nosten, Rintis Noviyanti, Alexis Nzila, Harold Ocholla, Abraham Oduro, Marie Onyamboko, Jean-Bosco Ouedraogo, Aung Pyae, Christopher Plowe, Ric Price, Sasithon Pukrittayakamee, Milijaona Randrianarivelojosia, Pascal Ringwald, Lastenia Ruiz, David Saunders, Alex Shayo, Peter Siba, Shannon Takala-Harrison, Thuy-Nhien Thanh, Vandana Thathy, Federica Verra, Jason Wendler, Nicholas White, Htut Ye, Victoria Cornelius, Rachel Giacomantonio, Dawn Muddyman, Christa Henrichs, Cinzia Malangone, Dushyanth Jyothi, Richard Pearson, Julian Rayner, Gilean McVean, Kirk Rockett, Alistair Miles, Paul Vauterin, Ben Jeffery, Magnus Manske, Jim Stalker, Bronwyn MacInnis, Dominic Kwiatkowski
Categories: malaria news feeds

Genomes of cryptic chimpanzee Plasmodium species reveal key evolutionary events leading to human malaria

CiteULike malaria tags - 24 March 2016 - 11:55am
Nature Communications, Vol. 7 (22 March 2016), 11078, doi:10.1038/ncomms11078
Sesh Sundararaman, Lindsey Plenderleith, Weimin Liu, Dorothy Loy, Gerald Learn, Yingying Li, Katharina Shaw, Ahidjo Ayouba, Martine Peeters, Sheri Speede, George Shaw, Frederic Bushman, Dustin Brisson, Julian Rayner, Paul Sharp, Beatrice Hahn
Categories: malaria news feeds

Transmission model of endemic human malaria in a partially immune population

CiteULike malaria tags - 21 March 2016 - 8:10pm
In Math. Comput. Model., Vol. 46, No. 5–6. (2007), 806-822, doi:10.1016/j.mcm.2006.12.010

A new transmission model of human malaria in a partially immune population with three discrete delays is formulated for variable host and vector populations. These are latent period in the host population, latent period in the vector population and duration of partial immunity. The results of our mathematical analysis indicate that a threshold parameter R 0 exists. For R 0 > 1 , the expected number of mosquitoes infected from humans R h m should be greater than a certain critical value R h m ∗ or should be less than R h m ∗ when R h m ∗ > 1 , for a stable endemic equilibrium to exist. We deduce from model analysis that an increase in the period within which partial immunity is lost increases the spread of the disease. Numerically we deduce that treatment of the partially immune humans assists in reducing the severity of the disease and that transmission blocking vaccines would be effective in a partially immune population. Numerical simulations support our analytical conclusions and illustrate possible behaviour scenarios of the model.
C Chiyaka, W Garira, S Dube
Categories: malaria news feeds

Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum

CiteULike malaria tags - 21 March 2016 - 3:35pm
Proc. R. Soc. B, Vol. 283, No. 1826. (16 March 2016), 20153038, doi:10.1098/rspb.2015.3038
Mary Bushman, Lindsay Morton, Nancy Duah, Neils Quashie, Benjamin Abuaku, Kwadwo Koram, Pedro Dimbu, Mateusz Plucinski, Julie Gutman, Peter Lyaruu, Patrick Kachur, Jacobus de Roode, Venkatachalam Udhayakumar
Categories: malaria news feeds

Landscape and Dynamics of Transcription Initiation in the Malaria Parasite Plasmodium falciparum

CiteULike malaria tags - 17 March 2016 - 10:33am
Cell Reports, Vol. 14, No. 10. (March 2016), pp. 2463-2475, doi:10.1016/j.celrep.2016.02.025

A genome-wide map of transcription start sites (TSSs) for P. falciparum Sequence and chromatin features for core promoters of malaria parasites are defined Dynamic study of TSS usage identifies developmentally regulated transcript isoforms A comprehensive map of transcription start sites (TSSs) across the highly AT-rich genome of P. falciparum would aid progress toward deciphering the molecular mechanisms that underlie the timely regulation of gene expression in this malaria parasite. Using high-throughput sequencing technologies, we generated a comprehensive atlas of transcription initiation events at single-nucleotide resolution during the parasite intra-erythrocytic developmental cycle. This detailed analysis of TSS usage enabled us to define architectural features of plasmodial promoters. We demonstrate that TSS selection and strength are constrained by local nucleotide composition. Furthermore, we provide evidence for coordinate and stage-specific TSS usage from distinct sites within the same transcription unit, thereby producing transcript isoforms, a subset of which are developmentally regulated. This work offers a framework for further investigations into the interactions between genomic sequences and regulatory factors governing the complex transcriptional program of this major human pathogen.
Sophie Adjalley, Christophe Chabbert, Bernd Klaus, Vicent Pelechano, Lars Steinmetz
Categories: malaria news feeds

A global bionomic database for the dominant vectors of human malaria

CiteULike malaria tags - 14 March 2016 - 2:51pm
Scientific Data, Vol. 3 (01 March 2016), doi:10.1038/sdata.2016.14

mosquitoes were first recognised as the transmitters of human malaria in the late 19th Century and have been subject to a huge amount of research ever since. Yet there is still much that is unknown regarding the ecology, behaviour (collectively âbionomicsâ) and sometimes even the identity of many of the worldâs most prominent disease vectors, much less the within-species variation in their bionomics. Whilst malaria elimination remains an ambitious goal, it is becoming increasingly clear that knowledge of vector behaviour is needed to effectively target control measures. A database of bionomics data for the dominant vector species of malaria worldwide has been compiled from published peer-reviewed literature. The data identification and collation processes are described, together with the geo-positioning and quality control methods. This is the only such dataset in existence and provides a valuable resource to researchers and policy makers in this field.
Claire Massey, Gala Garrod, Antoinette Wiebe, Andrew Henry, Zhi Huang, Catherine Moyes, Marianne Sinka
Categories: malaria news feeds