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

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

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

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

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.

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

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

Population genetic structure and adaptation of malaria parasites on the edge of endemic distribution

22 February 2017 - 10:26am
Mol Ecol (1 February 2017), pp. n/a-n/a, doi:10.1111/mec.14066

To determine whether the major human malaria parasite Plasmodium falciparum exhibits fragmented population structure or local adaptation at the northern limit of its African distribution where the dry Sahel zone meets the Sahara, samples were collected from diverse locations within Mauritania over a range of ~ 1000 kilometres. Microsatellite genotypes were obtained for 203 clinical infection samples from eight locations, and Illumina paired-end sequences were obtained to yield high coverage genome-wide single nucleotide polymorphism (SNP) data for 65 clinical infection samples from four locations. Most infections contained single parasite genotypes, reflecting low rates of transmission and superinfection locally, in contrast to the situation seen in population samples from countries further south. A minority of infections shared related or identical genotypes locally, indicating some repeated transmission of parasite clones without recombination. This caused some multi-locus linkage disequilibrium and local divergence, but aside from the effect of repeated genotypes there was minimal differentiation between locations. Several chromosomal regions had elevated integrated haplotype scores (|iHS|) indicating recent selection, including those containing drug resistance genes. A genome-wide FST scan comparison with previous sequence data from an area in West Africa with higher infection endemicity indicates that regional gene flow prevents genetic isolation, but revealed allele frequency differentiation at three drug resistance loci and an erythrocyte invasion ligand gene. Contrast of extended haplotype signatures revealed none to be unique to Mauritania. Discrete foci of infection on the edge of the Sahara are genetically highly connected to the wider continental parasite population, and local elimination would be difficult to achieve without very substantial reduction in malaria throughout the region. This article is protected by copyright. All rights reserved.
Craig Duffy, Hampate Ba, Samuel Assefa, Ambroise Ahouidi, Yacine Deh, Abderahmane Tandia, Freja Kirsebom, Dominic Kwiatkowski, David Conway
Categories: malaria news feeds

Single-cell transcriptomics of malaria parasites

17 February 2017 - 8:41am
bioRxiv (10 February 2017), 105015, doi:10.1101/105015

bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution
Adam Reid, Arthur Talman, Hayley Bennett, Ana Gomes, Mandy Sanders, Christopher Illingworth, Oliver Billker, Matthew Berriman, Mara Lawniczak
Categories: malaria news feeds

Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors.

16 February 2017 - 2:22pm
J. Clin. Invest., Vol. 122, No. 6. (2012), pp. 2301-2305, doi:10.1172/JCI61822

Effective control and eradication of malaria will require new tools to prevent transmission. Current antimalarial therapies targeting the asexual stage of Plasmodium do not prevent transmission of circulating gametocytes from infected humans to mosquitoes. Here, we describe a new class of transmission-blocking compounds, bumped kinase inhibitors (BKIs), which inhibit microgametocyte exflagellation. Oocyst formation and sporozoite production, necessary for transmission to mammals, were inhibited in mosquitoes fed on either BKI-1-treated human blood or mice treated with BKI-1. BKIs are hypothesized to act via inhibition of Plasmodium calcium-dependent protein kinase 4 and predicted to have little activity against mammalian kinases. Our data show that BKIs do not inhibit proliferation of mammalian cell lines and are well tolerated in mice. Used in combination with drugs active against asexual stages of Plasmodium, BKIs could prove an important tool for malaria control and eradication.
Kayode Ojo, Claudia Pfander, Natascha Mueller, Charlotte Burstroem, Eric Larson, Cassie Bryan, Anna Fox, Molly Reid, Steven Johnson, Ryan Murphy, Mark Kennedy, Henning Mann, David Leibly, Stephen Hewitt, Christophe Verlinde, Stefan Kappe, Ethan Merritt, Dustin Maly, Oliver Billker, Wesley Voorhis
Categories: malaria news feeds

Inhibition of the SR protein-phosphorylating CLK kinases of Plasmodium falciparum impairs blood stage replication and malaria transmission.

16 February 2017 - 2:22pm
PLoS ONE, Vol. 9, No. 9. (2014), doi:10.1371/journal.pone.0105732

Cyclin-dependent kinase-like kinases (CLKs) are dual specificity protein kinases that phosphorylate Serine/Arginine-rich (SR) proteins involved in pre-mRNA processing. Four CLKs, termed PfCLK-1-4, can be identified in the human malaria parasite Plasmodium falciparum, which show homology with the yeast SR protein kinase Sky1p. The four PfCLKs are present in the nucleus and cytoplasm of the asexual blood stages and of gametocytes, sexual precursor cells crucial for malaria parasite transmission from humans to mosquitoes. We identified three plasmodial SR proteins, PfSRSF12, PfSFRS4 and PfSF-1, which are predominantly present in the nucleus of blood stage trophozoites, PfSRSF12 and PfSF-1 are further detectable in the nucleus of gametocytes. We found that recombinantly expressed SR proteins comprising the Arginine/Serine (RS)-rich domains were phosphorylated by the four PfCLKs in in vitro kinase assays, while a recombinant PfSF-1 peptide lacking the RS-rich domain was not phosphorylated. Since it was hitherto not possible to knock-out the pfclk genes by conventional gene disruption, we aimed at chemical knock-outs for phenotype analysis. We identified five human CLK inhibitors, belonging to the oxo-$\β$-carbolines and aminopyrimidines, as well as the antiseptic chlorhexidine as PfCLK-targeting compounds. The six inhibitors block P. falciparum blood stage replication in the low micromolar to nanomolar range by preventing the trophozoite-to-schizont transformation. In addition, the inhibitors impair gametocyte maturation and gametogenesis in in vitro assays. The combined data show that the four PfCLKs are involved in phosphorylation of SR proteins with essential functions for the blood and sexual stages of the malaria parasite, thus pointing to the kinases as promising targets for antimalarial and transmission blocking drugs.
Selina Kern, Shruti Agarwal, Kilian Huber, André Gehring, Benjamin Strödke, Christine Wirth, Thomas Brügl, Liliane Abodo, Thomas Dandekar, Christian Doerig, Rainer Fischer, Andrew Tobin, Mahmood Alam, Franz Bracher, Gabriele Pradel
Categories: malaria news feeds

An atypical mitogen-activated protein kinase controls cytokinesis and flagellar motility during male gamete formation in a malaria parasite.

16 February 2017 - 2:22pm
Molecular Microbiology, Vol. 58, No. 5. (2005), pp. 1253-1263, doi:10.1111/j.1365-2958.2005.04793.x

The transmission of malaria parasites to the mosquito depends critically on the rapid initiation of sexual reproduction in response to triggers from the mosquito midgut environment. We here identify an essential function for an atypical mitogen-activated protein kinase of the rodent malaria parasite Plasmodium berghei, Pbmap-2, in male sexual differentiation and parasite transmission to the mosquito. A deletion mutant no longer expressing the Pbmap-2 protein develops as wild type throughout the asexual erythrocytic phase of the life cycle. Gametocytes, the sexual transmission stages, form normally and respond in vitro to the appropriate environmental cues by rounding up and emerging from their host cells. However, microgametocytes fail to release flagellated microgametes. Female development is not affected, as judged by the ability of macrogametes to become cross-fertilized by microgametes from a donor strain. Cellular differentiation of Pbmap-2 KO microgametocytes is blocked at a late stage of male gamete formation, after replication and mitoses have been completed and axonemes have been assembled. These data demonstrate a function for Pbmap-2 in initiating cytokinesis and axoneme motility, possibly downstream of a cell cycle checkpoint for the completion of replication and/or mitosis, which are extraordinarily rapid in the male gametocyte.
Rita Tewari, Dominique Dorin, Robert Moon, Christian Doerig, Oliver Billker
Categories: malaria news feeds

A mitogen-activated protein kinase regulates male gametogenesis and transmission of the malaria parasite Plasmodium berghei.

16 February 2017 - 2:22pm
EMBO Rep., Vol. 6, No. 5. (2005), pp. 464-469, doi:10.1038/sj.embor.7400404

Differentiation of malaria parasites into sexual forms (gametocytes) in the vertebrate host and their subsequent development into gametes in the mosquito vector are crucial steps in the completion of the parasite's life cycle and transmission of the disease. The molecular mechanisms that regulate the sexual cycle are poorly understood. Although several signal transduction pathways have been implicated, a clear understanding of the pathways involved has yet to emerge. Here, we show that a Plasmodium berghei homologue of Plasmodium falciparum mitogen-activated kinase-2 (Pfmap-2), a gametocyte-specific mitogen-activated protein kinase (MAPK), is required for male gamete formation. Parasites lacking Pbmap-2 are competent for gametocytogenesis, but exflagellation of male gametocytes, the process that leads to male gamete formation, is almost entirely abolished in mutant parasites. Consistent with this result, transmission of mutant parasites to mosquitoes is grossly impaired. This finding identifies a crucial role for a MAPK pathway in malaria transmission.
Radha Rangarajan, Amy Bei, Deepa Jethwaney, Priscilla Maldonado, Dominique Dorin, Ali Sultan, Christian Doerig
Categories: malaria news feeds

Plasmodium P-Type Cyclin CYC3 Modulates Endomitotic Growth during Oocyst Development in Mosquitoes.

16 February 2017 - 2:22pm
PLoS Pathog., Vol. 11, No. 11. (2015), doi:10.1371/journal.ppat.1005273

Cell-cycle progression and cell division in eukaryotes are governed in part by the cyclin family and their regulation of cyclin-dependent kinases (CDKs). Cyclins are very well characterised in model systems such as yeast and human cells, but surprisingly little is known about their number and role in Plasmodium, the unicellular protozoan parasite that causes malaria. Malaria parasite cell division and proliferation differs from that of many eukaryotes. During its life cycle it undergoes two types of mitosis: endomitosis in asexual stages and an extremely rapid mitotic process during male gametogenesis. Both schizogony (producing merozoites) in host liver and red blood cells, and sporogony (producing sporozoites) in the mosquito vector, are endomitotic with repeated nuclear replication, without chromosome condensation, before cell division. The role of specific cyclins during Plasmodium cell proliferation was unknown. We show here that the Plasmodium genome contains only three cyclin genes, representing an unusual repertoire of cyclin classes. Expression and reverse genetic analyses of the single Plant (P)-type cyclin, CYC3, in the rodent malaria parasite, Plasmodium berghei, revealed a cytoplasmic and nuclear location of the GFP-tagged protein throughout the lifecycle. Deletion of cyc3 resulted in defects in size, number and growth of oocysts, with abnormalities in budding and sporozoite formation. Furthermore, global transcript analysis of the cyc3-deleted and wild type parasites at gametocyte and ookinete stages identified differentially expressed genes required for signalling, invasion and oocyst development. Collectively these data suggest that cyc3 modulates oocyst endomitotic development in Plasmodium berghei.
Magali Roques, Richard Wall, Alexander Douglass, Abhinay Ramaprasad, David Ferguson, Mbinda Kaindama, Lorenzo Brusini, Nimitray Joshi, Zineb Rchiad, Declan Brady, David Guttery, Sally Wheatley, Hiroyuki Yamano, Anthony Holder, Arnab Pain, Bill Wickstead, Rita Tewari
Categories: malaria news feeds

Plasmodium falciparum NIMA-related kinase Pfnek-1: Sex specificity and assessment of essentiality for the erythrocytic asexual cycle.

16 February 2017 - 2:22pm
Microbiology, Vol. 157 (2011), pp. 2785-2794, doi:10.1099/mic.0.049023-0

The Plasmodium falciparum kinome includes a family of four protein kinases (Pfnek-1 to -4) related to the NIMA (never-in-mitosis) family, members of which play important roles in mitosis and meiosis in eukaryotic cells. Only one of these, Pfnek-1, which we previously characterized at the biochemical level, is expressed in asexual parasites. The other three (Pfnek-2, -3 and -4) are expressed predominantly in gametocytes, and a role for nek-2 and nek-4 in meiosis has been documented. Here we show by reverse genetics that Pfnek-1 is required for completion of the asexual cycle in red blood cells and that its expression in gametocytes in detectable by immunofluorescence in male (but not in female) gametocytes, in contrast with Pfnek-2 and Pfnek-4. This indicates that the function of Pfnek-1 is non-redundant with those of the other members of the Pfnek family and identifies Pfnek-1 as a potential target for antimalarial chemotherapy. A medium-throughput screen of a small-molecule library provides proof of concept that recombinant Pfnek-1 can be used as a target in drug discovery.
Dominique Dorin-Semblat, Sophie Schmitt, Jean-Philippe Semblat, Audrey Sicard, Luc Reininger, Dean Goldring, Shelley Patterson, Neils Quashie, Debopam Chakrabarti, Laurent Meijer, Christian Doerig
Categories: malaria news feeds

Nima- and Aurora-related kinases of malaria parasites.

16 February 2017 - 2:22pm
Biochimica et Biophysica Acta, Vol. 1834, No. 7. (2013), pp. 1336-1345, doi:10.1016/j.bbapap.2013.02.022

Completion of the life cycle of malaria parasite requires a succession of developmental stages which vary greatly with respect to proliferation status, implying a tightly regulated control of the parasite's cell cycle, which remains to be understood at the molecular level. Progression of the eukaryotic cell cycle is controlled by members of mitotic kinase of the families CDK (cyclin-dependent kinases), Aurora, Polo and NIMA. Plasmodium parasites possess cyclin-dependent protein kinases and cyclins, which strongly suggests that some of the principles underlying cell cycle control in higher eukaryotes also operate in this organism. However, atypical features of Plasmodium cell cycle organization and important divergences in the composition of the cell cycle machinery suggest the existence of regulatory mechanisms that are at variance with those of higher eukaryotes. This review focuses on several recently described Plasmodium protein kinases related to the NIMA and Aurora kinase families and discusses their functional involvement in parasite's biology. Given their demonstrated essential roles in the erythrocytic asexual cycle and/or sexual stages, these enzymes represent novel potential drug targets for antimalarial intervention aiming at inhibiting parasite replication and/or blocking transmission of the disease. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).
Teresa Carvalho, Christian Doerig, Luc Reininger
Categories: malaria news feeds

A genome-scale vector resource enables high-throughput reverse genetic screening in a malaria parasite.

16 February 2017 - 2:22pm
Cell Host Microbe, Vol. 17, No. 3. (2015), pp. 404-413, doi:10.1016/j.chom.2015.01.014

The genome-wide identification of gene functions in malaria parasites is hampered by a lack of reverse genetic screening methods. We present a large-scale resource of barcoded vectors with long homology arms for effective modification of the Plasmodium berghei genome. Cotransfecting dozens of vectors into the haploid blood stages creates complex pools of barcoded mutants, whose competitive fitness can be measured during infection of a single mouse using barcode sequencing (barseq). To validate the utility of this resource, we rescreen the P. berghei kinome, using published kinome screens for comparison. We find that several protein kinases function redundantly in asexual blood stages and confirm the targetability of kinases cdpk1, gsk3, tkl3, and PBANKA_082960 by genotyping cloned mutants. Thus, parallel phenotyping of barcoded mutants unlocks the power of reverse genetic screening for a malaria parasite and will enable the systematic identification of genes essential for in vivo parasite growth and transmission.
Ana Gomes, Ellen Bushell, Frank Schwach, Gareth Girling, Burcu Anar, Michael Quail, Colin Herd, Claudia Pfander, Katarzyna Modrzynska, Julian Rayner, Oliver Billker
Categories: malaria news feeds

Gene expression signatures and small-molecule compounds link a protein kinase to Plasmodium falciparum motility.

16 February 2017 - 2:22pm
Nat. Chem. Biol., Vol. 4, No. 6. (2008), pp. 347-356, doi:10.1038/nchembio.87

Calcium-dependent protein kinases play a crucial role in intracellular calcium signaling in plants, some algae and protozoa. In Plasmodium falciparum, calcium-dependent protein kinase 1 (PfCDPK1) is expressed during schizogony in the erythrocytic stage as well as in the sporozoite stage. It is coexpressed with genes that encode the parasite motor complex, a cellular component required for parasite invasion of host cells, parasite motility and potentially cytokinesis. A targeted gene-disruption approach demonstrated that pfcdpk1 seems to be essential for parasite viability. An in vitro biochemical screen using recombinant PfCDPK1 against a library of 20,000 compounds resulted in the identification of a series of structurally related 2,6,9-trisubstituted purines. Compound treatment caused sudden developmental arrest at the late schizont stage in P. falciparum and a large reduction in intracellular parasites in Toxoplasma gondii, which suggests a possible role for PfCDPK1 in regulation of parasite motility during egress and invasion.
Nobutaka Kato, Tomoyo Sakata, Ghislain Breton, Karine Roch, Advait Nagle, Carsten Andersen, Badry Bursulaya, Kerstin Henson, Jeffrey Johnson, Kota Kumar, Felix Marr, Daniel Mason, Case McNamara, David Plouffe, Vandana Ramachandran, Muriel Spooner, Tove Tuntland, Yingyao Zhou, Eric Peters, Arnab Chatterjee, Peter Schultz, Gary Ward, Nathanael Gray, Jeffrey Harper, Elizabeth Winzeler
Categories: malaria news feeds

Role of Plasmodium berghei cGMP-dependent protein kinase in late liver stage development.

16 February 2017 - 2:22pm
Journal of Biological Chemistry, Vol. 285, No. 5. (2010), pp. 3282-3288, doi:10.1074/jbc.M109.070367

The liver is the first organ infected by Plasmodium sporozoites during malaria infection. In the infected hepatocytes, sporozoites undergo a complex developmental program to eventually generate hepatic merozoites that are released into the bloodstream in membrane-bound vesicles termed merosomes. Parasites blocked at an early developmental stage inside hepatocytes elicit a protective host immune response, making them attractive targets in the effort to develop a pre-erythrocytic stage vaccine. Here, we generated parasites blocked at a late developmental stage inside hepatocytes by conditionally disrupting the Plasmodium berghei cGMP-dependent protein kinase in sporozoites. Mutant sporozoites are able to invade hepatocytes and undergo intracellular development. However, they remain blocked as late liver stages that do not release merosomes into the medium. These late arrested liver stages induce protection in immunized animals. This suggests that, similar to the well studied early liver stages, late stage liver stages too can confer protection from sporozoite challenge.
Adebola Falae, Audrey Combe, Anburaj Amaladoss, Teresa Carvalho, Robert Menard, Purnima Bhanot
Categories: malaria news feeds

The malaria parasite cyclic GMP-dependent protein kinase plays a central role in blood-stage schizogony.

16 February 2017 - 2:22pm
Eukaryotic Cell, Vol. 9, No. 1. (2010), pp. 37-45, doi:10.1128/EC.00186-09

A role for the Plasmodium falciparum cyclic GMP (cGMP)-dependent protein kinase (PfPKG) in gametogenesis in the malaria parasite was elucidated previously. In the present study we examined the role of PfPKG in the asexual blood-stage of the parasite life cycle, the stage that causes malaria pathology. A specific PKG inhibitor (compound 1, a trisubstituted pyrrole) prevented the progression of P. falciparum schizonts through to ring stages in erythrocyte invasion assays. Addition of compound 1 to ring-stage parasites allowed normal development up to 30 h postinvasion, and segmented schizonts were able to form. However, synchronized schizonts treated with compound 1 for > or =6 h became large and dysmorphic and were unable to rupture or liberate merozoites. To conclusively demonstrate that the effect of compound 1 on schizogony was due to its selective action on PfPKG, we utilized genetically manipulated P. falciparum parasites expressing a compound 1-insensitive PfPKG. The mutant parasites were able to complete schizogony in the presence of compound 1 but not in the presence of the broad-spectrum protein kinase inhibitor staurosporine. This shows that PfPKG is the primary target of compound 1 during schizogony and provides direct evidence of a role for PfPKG in this process. Discovery of essential roles for the P. falciparum PKG in both asexual and sexual development demonstrates that cGMP signaling is a key regulator of both of these crucial life cycle phases and defines this molecule as an exciting potential drug target for both therapeutic and transmission blocking action against malaria.
Helen Taylor, Louisa McRobert, Munira Grainger, Audrey Sicard, Anton Dluzewski, Christine Hopp, Anthony Holder, David Baker
Categories: malaria news feeds

The coming-out of malaria gametocytes.

16 February 2017 - 2:22pm
J. Biomed. Biotechnol., Vol. 2010 (2010), doi:10.1155/2010/976827

The tropical disease malaria, which results in more than one million deaths annually, is caused by protozoan parasites of the genus Plasmodium and transmitted by blood-feeding Anopheline mosquitoes. Parasite transition from the human host to the mosquito vector is mediated by gametocytes, sexual stages that are formed in human erythrocytes, which therefore play a crucial part in the spread of the tropical disease. The uptake by the blood-feeding mosquito triggers important molecular and cellular changes in the gametocytes, thus mediating the rapid adjustment of the parasite from the warm-blooded host to the insect host and subsequently initiating reproduction. The contact with midgut factors triggers gametocyte activation and results in their egress from the enveloping erythrocyte, which then leads to gamete formation and fertilization. This review summarizes recent findings on the role of gametocytes during transmission to the mosquito and particularly focuses on the molecular mechanisms underlying gametocyte activation and emergence from the host erythrocyte during gametogenesis.
A Kuehn, G Pradel
Categories: malaria news feeds

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