Billker Group
Our Research and Approach
The development of new drugs and vaccines against malaria poses one of the major challenges to current medical research. It must be grounded in the thorough understanding of the parasite's biology, including its interactions with the host, and the Anopheles mosquitoes that transmit it. P. berghei provides a highly tractable model to study the fundamental cell biology of malaria parasites and many aspects of their interactions with host and vector.
During the team's time at the Sanger Institue, we were particularly interested to learn how the cellular processes involved in sexual development and mosquito transmission are regulated through signal transduction pathways that control stage conversion, gene transcription and protein translation. To achieve this we often combined the global analysis of all other genes and proteins in the parasite cell with the targeted modification of one carefully chosen parasite gene. We also systematically analysed all parasite proteins for modifications that alter their function, such as the addition of phosphate or lipids.
Using these approaches we discovered a regulator of gene expression that functions as the master switch for the formation parasite stages in the blood that are essential to transmit Plasmodium to the mosquito (Sinha et al., 2014). We also found out that the same biochemical pathway regulates many different aspects of parasite biology by linking two intracellular messengers, calcium and a cyclic nucleotide (Brochet et al., 2014). We also showed how such discoveries can be exploited for drug development by demonstrating that a drug-like chemical inhibitor of a calcium dependent protein kinase can block malaria transmission to mosquitoes when administered to a mouse (Ojo et al., 2012).
The targeted modification of the genome is far more difficult in malaria parasites than in model organisms, such as yeast. To increase the rate at which discoveries can be made in P. berghei, we have developed protocols to produce more efficient genetic modification vectors and other molecular tools that allow researchers to rapidly switch parasite genes on and off. A production pipeline has now produced a genome scale set of gene knock out and tagging vectors for the P. berghei genome and pilot projects are well underway for other Plasmodium species. These resources are freely available to all researchers and can be viewed through the PlasmoGEM database. We also developed protocols to use PlasmoGEM vectors in genetic screens that query the functions of thousands of parasite genes at the same time. PlasmoGEM is a joint project with the Rayner group. It relies heavily on the reference genomes produced by Matt Berriman's Parasite Genomics team.
People
Bronner-Anar, Burcu
Burcu Bronner-Anar, MSc
Girling, Gareth
Mr Gareth Girling
Muraro, Daniele
Dr Daniele Muraro
Russell, Andrew J C
Andrew J C Russell
Sayers, Claire
Dr Claire Sayers
Schwach, Frank
Dr Frank Schwach
Alumni
Bushell, Ellen
Dr Ellen Bushell
Marsden, Sarah
Sarah Marsden, MSc
Montandon, Ruddy
Ruddy Montandon
Raddi, Gianmarco

Gianmarco Raddi
Key Projects, Collaborations, Tools & Data
Programmes, Associate Research Programmes and Facilities
Partners and Funders
Internal Partners
Publications
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A genome-scale vector resource enables high-throughput reverse genetic screening in a malaria parasite.
Cell host & microbe 2015;17;3;404-413
PUBMED: 25732065; PMC: 4362957; DOI: 10.1016/j.chom.2015.01.014
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A comprehensive evaluation of rodent malaria parasite genomes and gene expression.
BMC biology 2014;12;86
PUBMED: 25359557; PMC: 4242472; DOI: 10.1186/s12915-014-0086-0
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Phosphoinositide metabolism links cGMP-dependent protein kinase G to essential Ca²⁺ signals at key decision points in the life cycle of malaria parasites.
PLoS biology 2014;12;3;e1001806
PUBMED: 24594931; PMC: 3942320; DOI: 10.1371/journal.pbio.1001806
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A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium.
Nature 2014;507;7491;253-257
PUBMED: 24572359; PMC: 4105895; DOI: 10.1038/nature12970
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Comparative genomics in Chlamydomonas and Plasmodium identifies an ancient nuclear envelope protein family essential for sexual reproduction in protists, fungi, plants, and vertebrates.
Genes & development 2013;27;10;1198-215
PUBMED: 23699412; PMC: 3672651; DOI: 10.1101/gad.212746.112
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A tetracycline-repressible transactivator system to study essential genes in malaria parasites.
Cell host & microbe 2012;12;6;824-34
PUBMED: 23245327; PMC: 3712325; DOI: 10.1016/j.chom.2012.10.016
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A Plasmodium calcium-dependent protein kinase controls zygote development and transmission by translationally activating repressed mRNAs.
Cell host & microbe 2012;12;1;9-19
PUBMED: 22817984; PMC: 3414820; DOI: 10.1016/j.chom.2012.05.014
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A scalable pipeline for highly effective genetic modification of a malaria parasite.
Nature methods 2011;8;12;1078-82
PUBMED: 22020067; PMC: 3431185; DOI: 10.1038/nmeth.1742
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The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission.
Cell host & microbe 2010;8;4;377-87
PUBMED: 20951971; PMC: 2977076; DOI: 10.1016/j.chom.2010.09.006
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The conserved plant sterility gene HAP2 functions after attachment of fusogenic membranes in Chlamydomonas and Plasmodium gametes.
Genes & development 2008;22;8;1051-68
PUBMED: 18367645; PMC: 2335326; DOI: 10.1101/gad.1656508
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Calcium and a calcium-dependent protein kinase regulate gamete formation and mosquito transmission in a malaria parasite.
Cell 2004;117;4;503-14
PUBMED: 15137943; DOI: 10.1016/s0092-8674(04)00449-0
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Distinct mechanisms of internalization of Neisseria gonorrhoeae by members of the CEACAM receptor family involving Rac1- and Cdc42-dependent and -independent pathways.
The EMBO journal 2002;21;4;560-71
PUBMED: 11847104; PMC: 125849; DOI: 10.1093/emboj/21.4.560
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Identification of xanthurenic acid as the putative inducer of malaria development in the mosquito.
Nature 1998;392;6673;289-92
PUBMED: 9521324; DOI: 10.1038/32667
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Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage.
Cell 2019;179;5;1112-1128.e26
PUBMED: 31730853; DOI: 10.1016/j.cell.2019.10.030
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The Malaria Cell Atlas: Single parasite transcriptomes across the complete Plasmodium life cycle.
Science (New York, N.Y.) 2019;365;6455
PUBMED: 31439762; DOI: 10.1126/science.aaw2619
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Inducible developmental reprogramming redefines commitment to sexual development in the malaria parasite Plasmodium berghei.
Nature microbiology 2018
PUBMED: 30177743; DOI: 10.1038/s41564-018-0223-6
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Proteomic profiling of the brain of mice with experimental cerebral malaria.
Journal of proteomics 2018;180;61-69
PUBMED: 28602553; DOI: 10.1016/j.jprot.2017.06.002
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Alpha-v-containing integrins are host receptors for the Plasmodium falciparum sporozoite surface protein, TRAP.
Proceedings of the National Academy of Sciences of the United States of America 2018;115;17;4477-4482
PUBMED: 29632205; PMC: 5924908; DOI: 10.1073/pnas.1719660115
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Complete avian malaria parasite genomes reveal features associated with lineage-specific evolution in birds and mammals.
Genome research 2018;28;4;547-560
PUBMED: 29500236; PMC: 5880244; DOI: 10.1101/gr.218123.116
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Single-cell RNA-seq reveals hidden transcriptional variation in malaria parasites.
eLife 2018;7
PUBMED: 29580379; PMC: 5871331; DOI: 10.7554/eLife.33105
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Sub-minute Phosphoregulation of Cell Cycle Systems during Plasmodium Gamete Formation.
Cell reports 2017;21;7;2017-2029
PUBMED: 29141230; DOI: 10.1016/j.celrep.2017.10.071
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Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes.
Cell 2017;170;2;260-272.e8
PUBMED: 28708996; PMC: 5509546; DOI: 10.1016/j.cell.2017.06.030
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Nutrient sensing modulates malaria parasite virulence.
Nature 2017;547;7662;213-216
PUBMED: 28678779; PMC: 5511512; DOI: 10.1038/nature23009
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Single-cell RNA-seq and computational analysis using temporal mixture modelling resolves Th1/Tfh fate bifurcation in malaria.
Science immunology 2017;2;9
PUBMED: 28345074; PMC: 5365145; DOI: 10.1126/sciimmunol.aal2192
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Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria.
The Journal of infectious diseases 2016;214;12;1840-1849
PUBMED: 27923948; DOI: 10.1093/infdis/jiw452
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Invasion of hepatocytes by Plasmodium sporozoites requires cGMP-dependent protein kinase and calcium dependent protein kinase 4.
Molecular microbiology 2016;102;2;349-363
PUBMED: 27425827; DOI: 10.1111/mmi.13466
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Palmitoyl Transferases have Critical Roles in the Development of Mosquito and Liver Stages of Plasmodium.
Cellular microbiology 2016
PUBMED: 27084458; DOI: 10.1111/cmi.12601
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Calcium signalling in malaria parasites.
Molecular microbiology 2016
PUBMED: 26748879; DOI: 10.1111/mmi.13324
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A Stem Cell Strategy Identifies Glycophorin C as a Major Erythrocyte Receptor for the Rodent Malaria Parasite Plasmodium berghei.
PloS one 2016;11;6;e0158238
PUBMED: 27362409; PMC: 4928779; DOI: 10.1371/journal.pone.0158238
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Enhanced Methylation Analysis by Recovery of Unsequenceable Fragments.
PloS one 2016;11;3;e0152322
PUBMED: 27031619; PMC: 4816320; DOI: 10.1371/journal.pone.0152322
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The Kinomics of Malaria
Kinomics: Approaches and Applications 2015;115-136
DOI: 10.1002/9783527683031.ch5; URL: http://onlinelibrary.wiley.com/doi/...10.1002/9783527683031.ch5/summary;jsessionid=C130139C5D6D8E5170FE3ADA2019D894.f01t03
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Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.
PLoS pathogens 2015;11;9;e1005119
PUBMED: 26407009; PMC: 4583463; DOI: 10.1371/journal.ppat.1005119
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Calcium Builds Strong Host-Parasite Interactions.
Cell host & microbe 2015;18;1;9-10
PUBMED: 26159715; DOI: 10.1016/j.chom.2015.06.012
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A genome-scale vector resource enables high-throughput reverse genetic screening in a malaria parasite.
Cell host & microbe 2015;17;3;404-413
PUBMED: 25732065; PMC: 4362957; DOI: 10.1016/j.chom.2015.01.014
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Conditional-ready mouse embryonic stem cell derived macrophages enable the study of essential genes in macrophage function.
Scientific reports 2015;5;8908
PUBMED: 25752829; PMC: 4354151; DOI: 10.1038/srep08908
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PlasmoGEM, a database supporting a community resource for large-scale experimental genetics in malaria parasites.
Nucleic acids research 2015;43;Database issue;D1176-82
PUBMED: 25593348; PMC: 4383951; DOI: 10.1093/nar/gku1143
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A comprehensive evaluation of rodent malaria parasite genomes and gene expression.
BMC biology 2014;12;86
PUBMED: 25359557; PMC: 4242472; DOI: 10.1186/s12915-014-0086-0
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BCKDH: the missing link in apicomplexan mitochondrial metabolism is required for full virulence of Toxoplasma gondii and Plasmodium berghei.
PLoS pathogens 2014;10;7;e1004263
PUBMED: 25032958; PMC: 4102578; DOI: 10.1371/journal.ppat.1004263
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A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium.
Nature 2014;507;7491;253-257
PUBMED: 24572359; PMC: 4105895; DOI: 10.1038/nature12970
-
Phosphoinositide metabolism links cGMP-dependent protein kinase G to essential Ca²⁺ signals at key decision points in the life cycle of malaria parasites.
PLoS biology 2014;12;3;e1001806
PUBMED: 24594931; PMC: 3942320; DOI: 10.1371/journal.pbio.1001806
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Efficacy of a Plasmodium vivax malaria vaccine using ChAd63 and modified vaccinia Ankara expressing thrombospondin-related anonymous protein as assessed with transgenic Plasmodium berghei parasites.
Infection and immunity 2014;82;3;1277-86
PUBMED: 24379295; PMC: 3957994; DOI: 10.1128/IAI.01187-13
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Global analysis of apicomplexan protein S-acyl transferases reveals an enzyme essential for invasion.
Traffic (Copenhagen, Denmark) 2013;14;8;895-911
PUBMED: 23638681; PMC: 3813974; DOI: 10.1111/tra.12081
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Comparative genomics in Chlamydomonas and Plasmodium identifies an ancient nuclear envelope protein family essential for sexual reproduction in protists, fungi, plants, and vertebrates.
Genes & development 2013;27;10;1198-215
PUBMED: 23699412; PMC: 3672651; DOI: 10.1101/gad.212746.112
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Defining the range of pathogens susceptible to Ifitm3 restriction using a knockout mouse model.
PloS one 2013;8;11;e80723
PUBMED: 24278312; PMC: 3836756; DOI: 10.1371/journal.pone.0080723
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Recombination-mediated genetic engineering of Plasmodium berghei DNA.
Methods in molecular biology (Clifton, N.J.) 2013;923;127-38
PUBMED: 22990774; DOI: 10.1007/978-1-62703-026-7_8
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A tetracycline-repressible transactivator system to study essential genes in malaria parasites.
Cell host & microbe 2012;12;6;824-34
PUBMED: 23245327; PMC: 3712325; DOI: 10.1016/j.chom.2012.10.016
-
A Plasmodium calcium-dependent protein kinase controls zygote development and transmission by translationally activating repressed mRNAs.
Cell host & microbe 2012;12;1;9-19
PUBMED: 22817984; PMC: 3414820; DOI: 10.1016/j.chom.2012.05.014
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Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors.
The Journal of clinical investigation 2012;122;6;2301-5
PUBMED: 22565309; PMC: 3366411; DOI: 10.1172/JCI61822
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A scalable pipeline for highly effective genetic modification of a malaria parasite.
Nature methods 2011;8;12;1078-82
PUBMED: 22020067; PMC: 3431185; DOI: 10.1038/nmeth.1742
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Genetic and transcriptional analysis of phosphoinositide-specific phospholipase C in Plasmodium.
Experimental parasitology 2011;129;1;75-80
PUBMED: 21651909; DOI: 10.1016/j.exppara.2011.05.023
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Multiple roles for Plasmodium berghei phosphoinositide-specific phospholipase C in regulating gametocyte activation and differentiation.
Cellular microbiology 2011;13;7;955-66
PUBMED: 21518218; PMC: 3132445; DOI: 10.1111/j.1462-5822.2011.01591.x
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Cutting edge: the membrane attack complex of complement is required for the development of murine experimental cerebral malaria.
Journal of immunology (Baltimore, Md. : 1950) 2011;186;12;6657-60
PUBMED: 21572031; PMC: 3110530; DOI: 10.4049/jimmunol.1100603
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A research agenda for malaria eradication: basic science and enabling technologies.
PLoS medicine 2011;8;1;e1000399
PUBMED: 21311584; PMC: 3026698; DOI: 10.1371/journal.pmed.1000399
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The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission.
Cell host & microbe 2010;8;4;377-87
PUBMED: 20951971; PMC: 2977076; DOI: 10.1016/j.chom.2010.09.006
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A parasite calcium switch and Achilles' heel revealed.
Nature structural & molecular biology 2010;17;5;541-3
PUBMED: 20442739; DOI: 10.1038/nsmb0510-541
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Quantitative assessment of DNA replication to monitor microgametogenesis in Plasmodium berghei.
Molecular and biochemical parasitology 2009;168;2;172-6
PUBMED: 19712704; PMC: 2789244; DOI: 10.1016/j.molbiopara.2009.08.004
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A cyclic GMP signalling module that regulates gliding motility in a malaria parasite.
PLoS pathogens 2009;5;9;e1000599
PUBMED: 19779564; PMC: 2742896; DOI: 10.1371/journal.ppat.1000599
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Signalling in malaria parasites. The MALSIG consortium.
Parasite (Paris, France) 2009;16;3;169-82
PUBMED: 19839262
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An essential role for the Plasmodium Nek-2 Nima-related protein kinase in the sexual development of malaria parasites.
The Journal of biological chemistry 2009;284;31;20858-68
PUBMED: 19491095; PMC: 2742851; DOI: 10.1074/jbc.M109.017988
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Calcium-dependent signaling and kinases in apicomplexan parasites.
Cell host & microbe 2009;5;6;612-22
PUBMED: 19527888; PMC: 2718762; DOI: 10.1016/j.chom.2009.05.017
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Protein kinases of malaria parasites: an update.
Trends in parasitology 2008;24;12;570-7
PUBMED: 18845480; DOI: 10.1016/j.pt.2008.08.007
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Gametogenesis in malaria parasites is mediated by the cGMP-dependent protein kinase.
PLoS biology 2008;6;6;e139
PUBMED: 18532880; PMC: 2408617; DOI: 10.1371/journal.pbio.0060139
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The conserved plant sterility gene HAP2 functions after attachment of fusogenic membranes in Chlamydomonas and Plasmodium gametes.
Genes & development 2008;22;8;1051-68
PUBMED: 18367645; PMC: 2335326; DOI: 10.1101/gad.1656508
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Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade host cells.
Cell host & microbe 2007;2;5;316-27
PUBMED: 18005753; PMC: 2117360; DOI: 10.1016/j.chom.2007.10.002
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Plasmodium berghei calcium-dependent protein kinase 3 is required for ookinete gliding motility and mosquito midgut invasion.
Molecular microbiology 2006;60;6;1355-63
PUBMED: 16796674; PMC: 1513514; DOI: 10.1111/j.1365-2958.2006.05189.x
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Generation of gene targeting constructs for Plasmodium berghei by a PCR-based method amenable to high throughput applications.
Molecular and biochemical parasitology 2006;145;2;265-8
PUBMED: 16290088; DOI: 10.1016/j.molbiopara.2005.10.006
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Protein kinases as targets for antimalarial intervention: Kinomics, structure-based design, transmission-blockade, and targeting host cell enzymes.
Biochimica et biophysica acta 2005;1754;1-2;132-50
PUBMED: 16271522; DOI: 10.1016/j.bbapap.2005.08.027
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An atypical mitogen-activated protein kinase controls cytokinesis and flagellar motility during male gamete formation in a malaria parasite.
Molecular microbiology 2005;58;5;1253-63
PUBMED: 16313614; DOI: 10.1111/j.1365-2958.2005.04793.x
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A NIMA-related protein kinase is essential for completion of the sexual cycle of malaria parasites.
The Journal of biological chemistry 2005;280;36;31957-64
PUBMED: 15970588; DOI: 10.1074/jbc.M504523200
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Calcium and a calcium-dependent protein kinase regulate gamete formation and mosquito transmission in a malaria parasite.
Cell 2004;117;4;503-14
PUBMED: 15137943; DOI: 10.1016/s0092-8674(04)00449-0
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Differential recognition of members of the carcinoembryonic antigen family by Afa/Dr adhesins of diffusely adhering Escherichia coli (Afa/Dr DAEC).
Molecular microbiology 2004;52;4;963-83
PUBMED: 15130118; DOI: 10.1111/j.1365-2958.2004.04033.x
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The dynamics of interactions between Plasmodium and the mosquito: a study of the infectivity of Plasmodium berghei and Plasmodium gallinaceum, and their transmission by Anopheles stephensi, Anopheles gambiae and Aedes aegypti.
International journal for parasitology 2003;33;9;933-43
PUBMED: 12906877
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Azadirachtin disrupts formation of organised microtubule arrays during microgametogenesis of Plasmodium berghei.
The Journal of eukaryotic microbiology 2002;49;6;489-97
PUBMED: 12503686
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Nuclear factor-kappa B directs carcinoembryonic antigen-related cellular adhesion molecule 1 receptor expression in Neisseria gonorrhoeae-infected epithelial cells.
The Journal of biological chemistry 2002;277;9;7438-46
PUBMED: 11751883; DOI: 10.1074/jbc.M108135200
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Distinct mechanisms of internalization of Neisseria gonorrhoeae by members of the CEACAM receptor family involving Rac1- and Cdc42-dependent and -independent pathways.
The EMBO journal 2002;21;4;560-71
PUBMED: 11847104; PMC: 125849; DOI: 10.1093/emboj/21.4.560
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Signal transduction pathways induced by virulence factors of Neisseria gonorrhoeae.
International journal of medical microbiology : IJMM 2001;291;4;307-14
PUBMED: 11680791; DOI: 10.1078/1438-4221-00134
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Both mosquito-derived xanthurenic acid and a host blood-derived factor regulate gametogenesis of Plasmodium in the midgut of the mosquito.
Molecular and biochemical parasitology 2001;116;1;17-24
PUBMED: 11463462
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The structural basis of CEACAM-receptor targeting by neisserial Opa proteins.
Trends in microbiology 2000;8;6;258-60; discussion 260-1
PUBMED: 10838580
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Determination of mosquito bloodmeal pH in situ by ion-selective microelectrode measurement: implications for the regulation of malarial gametogenesis.
Parasitology 2000;120 ( Pt 6);547-51
PUBMED: 10874717