Billker Group

Sanger Institute, Genome Research Limited

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.

We are 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 combine 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 analyse all parasite proteins for modifications that alter their function, such as the addition of phosphate or lipids.

This 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 are now developing 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.

Tools and resources for P. berghei genetic modification.

We have generated arrayed libraries of P. berghei genomic DNA with average inserts of ca. 8.5 kb. These are large inserts, considering that P. berghei DNA is very AT-rich, making it highly unstable in E. coli. We also developed a set of tools and protocols to engineer genomic DNA in E. coli with the help of transiently expressed phage recombinases, a process termed recombineering. These protocols are robust enough to work on 96-well plates. They allow us to turn library clones into complex genetic modification vectors at scale. Using this technology we are now producing genome-wide sets of genetic modification vectors and make these available as a free resource.

PlasmoGEM vectors have advantages over conventional designs: due to their long homology arms they integrate very efficiently. Furthermore, since the vectors never exist in a circular form, targeting essential genes does not select for episomes, thereby eliminating a major source of false positive results. The advantages of PlasmoGEM vectors now make it possible to generate complex mixtures of mutant parasites. Since each PlasmoGEM vector carries a gene-specific molecular barcode which can be read out and counted on a DNA sequencer, we can now study the growth of hundreds or even thousands of parasites in a single mouse.

We will now use this barcode counting strategy to design genetic screens. Using this approach we will be able to establish, for instance, which enzymatic pathways malaria parasites require to replicate in their different hosts, which parasite genes are needed for transmission to the mosquito, or which parasite genes are involved when an infection leads to severe disease.

Signal Transduction Pathways Regulating Sexual Development

Sexual development in Plasmodium is tightly linked to transmission by mosquitoes. We recently discovered a master regulator of sexual development (Sinha et al., 2014). Now we need to work out how this switch works and how it can be controlled by host factors. We are also screening more transcription factors and signalling proteins systematically to discover similarly important regulators of parasite development. Various projects now generate a deep understanding of some of our mutants through comparative analysis of transcriptomes, proteomes and secondary protein modifications, such as phosphorylation (Sebastian et al., 2012; Brochet et al., 2014).

Host Genes Regulating Parasite Development

There is an urgent need for new experimental models that can identify the role of host genes in parasite-host interactions. As genome-wide association studies discover more of the relevant natural genetic variation in human populations that controls susceptibility to malaria (Natural Genetic Variation), new tools to identify the underlying molecular mechanisms will be required. Some projects in the lab are developed jointly with the Cellular Genetics Programme to explore the use of in vitro differentiated mouse embryonic stem cells and human iPS cells to get at this problem.

People

Dr Oliver Billker

Group Leader

Oliver develops new genetic technologies to investigate how malaria parasites reproduce in mosquitoes and get transmitted.

Key Projects, Collaborations, Tools & Data

Research Programmes

Partners and Funders

Internal Partners

Publications

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

Gomes AR, Bushell E, Schwach F, Girling G, Anar B et al.

Cell host & microbe 2015;17;3;404-413

PUBMED: 25732065; PMC: 4362957; DOI: 10.1016/j.chom.2015.01.014
A comprehensive evaluation of rodent malaria parasite genomes and gene expression.

Otto TD, Böhme U, Jackson AP, Hunt M, Franke-Fayard B et al.

BMC biology 2014;12;86

PUBMED: 25359557; PMC: 4242472; DOI: 10.1186/s12915-014-0086-0
Phosphoinositide metabolism links cGMP-dependent protein kinase G to essential Ca²⁺ signals at key decision points in the life cycle of malaria parasites.

Brochet M, Collins MO, Smith TK, Thompson E, Sebastian S et al.

PLoS biology 2014;12;3;e1001806

PUBMED: 24594931; PMC: 3942320; DOI: 10.1371/journal.pbio.1001806
A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium.

Sinha A, Hughes KR, Modrzynska KK, Otto TD, Pfander C et al.

Nature 2014;507;7491;253-257

PUBMED: 24572359; PMC: 4105895; DOI: 10.1038/nature12970
Comparative genomics in Chlamydomonas and Plasmodium identifies an ancient nuclear envelope protein family essential for sexual reproduction in protists, fungi, plants, and vertebrates.

Ning J, Otto TD, Pfander C, Schwach F, Brochet M et al.

Genes & development 2013;27;10;1198-215

PUBMED: 23699412; PMC: 3672651; DOI: 10.1101/gad.212746.112
A tetracycline-repressible transactivator system to study essential genes in malaria parasites.

Pino P, Sebastian S, Kim EA, Bush E, Brochet M et al.

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.

Sebastian S, Brochet M, Collins MO, Schwach F, Jones ML et al.

Cell host & microbe 2012;12;1;9-19

PUBMED: 22817984; PMC: 3414820; DOI: 10.1016/j.chom.2012.05.014
A scalable pipeline for highly effective genetic modification of a malaria parasite.

Pfander C, Anar B, Schwach F, Otto TD, Brochet M et al.

Nature methods 2011;8;12;1078-82

PUBMED: 22020067; PMC: 3431185; DOI: 10.1038/nmeth.1742
The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission.

Tewari R, Straschil U, Bateman A, Böhme U, Cherevach I et al.

Cell host & microbe 2010;8;4;377-87

PUBMED: 20951971; PMC: 2977076; DOI: 10.1016/j.chom.2010.09.006
The conserved plant sterility gene HAP2 functions after attachment of fusogenic membranes in Chlamydomonas and Plasmodium gametes.

Liu Y, Tewari R, Ning J, Blagborough AM, Garbom S et al.

Genes & development 2008;22;8;1051-68

PUBMED: 18367645; PMC: 2335326; DOI: 10.1101/gad.1656508
Calcium and a calcium-dependent protein kinase regulate gamete formation and mosquito transmission in a malaria parasite.

Billker O, Dechamps S, Tewari R, Wenig G, Franke-Fayard B and Brinkmann V

Cell 2004;117;4;503-14

PUBMED: 15137943
Distinct mechanisms of internalization of Neisseria gonorrhoeae by members of the CEACAM receptor family involving Rac1- and Cdc42-dependent and -independent pathways.

Billker O, Popp A, Brinkmann V, Wenig G, Schneider J et al.

The EMBO journal 2002;21;4;560-71

PUBMED: 11847104; PMC: 125849
Identification of xanthurenic acid as the putative inducer of malaria development in the mosquito.

Billker O, Lindo V, Panico M, Etienne AE, Paxton T et al.

Nature 1998;392;6673;289-92

PUBMED: 9521324; DOI: 10.1038/32667

Alpha-v-containing integrins are host receptors for the <i>Plasmodium falciparum</i> sporozoite surface protein, TRAP.

Dundas K, Shears MJ, Sun Y, Hopp CS, Crosnier C et al.

Proceedings of the National Academy of Sciences of the United States of America 2018

PUBMED: 29632205; DOI: 10.1073/pnas.1719660115
Complete avian malaria parasite genomes reveal features associated with lineage-specific evolution in birds and mammals.

Böhme U, Otto TD, Cotton JA, Steinbiss S, Sanders M et al.

Genome research 2018;28;4;547-560

PUBMED: 29500236; PMC: 5880244; DOI: 10.1101/gr.218123.116
Single-cell RNA-seq reveals hidden transcriptional variation in malaria parasites.

Reid AJ, Talman AM, Bennett HM, Gomes AR, Sanders MJ et al.

eLife 2018;7

PUBMED: 29580379; DOI: 10.7554/eLife.33105

Sub-minute Phosphoregulation of Cell Cycle Systems during Plasmodium Gamete Formation.

Invergo BM, Brochet M, Yu L, Choudhary J, Beltrao P and Billker O

Cell reports 2017;21;7;2017-2029

PUBMED: 29141230; DOI: 10.1016/j.celrep.2017.10.071
Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes.

Bushell E, Gomes AR, Sanderson T, Anar B, Girling G et al.

Cell 2017;170;2;260-272.e8

PUBMED: 28708996; PMC: 5509546; DOI: 10.1016/j.cell.2017.06.030
Nutrient sensing modulates malaria parasite virulence.

Mancio-Silva L, Slavic K, Grilo Ruivo MT, Grosso AR, Modrzynska KK et al.

Nature 2017;547;7662;213-216

PUBMED: 28678779; PMC: 5511512; DOI: 10.1038/nature23009
Proteomic profiling of the brain of mice with experimental cerebral malaria.

Moussa E, Huang H, Ahras M, Lall A, Thezenas ML et al.

Journal of proteomics 2017

PUBMED: 28602553; DOI: 10.1016/j.jprot.2017.06.002
Single-cell RNA-seq and computational analysis using temporal mixture modelling resolves Th1/Tfh fate bifurcation in malaria.

Lönnberg T, Svensson V, James KR, Fernandez-Ruiz D, Sebina I et al.

Science immunology 2017;2;9

PUBMED: 28345074; PMC: 5365145; DOI: 10.1126/sciimmunol.aal2192

Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria.

Alkaitis MS, Wang H, Ikeda AK, Rowley CA, MacCormick IJ et al.

The Journal of infectious diseases 2016;214;12;1840-1849

PUBMED: 27923948; DOI: 10.1093/infdis/jiw452
Invasion of hepatocytes by Plasmodium sporozoites requires cGMP-dependent protein kinase and calcium dependent protein kinase 4.

Govindasamy K, Jebiwott S, Jaijyan DK, Davidow A, Ojo KK et al.

Molecular microbiology 2016

PUBMED: 27425827; DOI: 10.1111/mmi.13466
Palmitoyl Transferases have Critical Roles in the Development of Mosquito and Liver Stages of Plasmodium.

Hopp CS, Balaban AE, Bushell E, Billker O, Rayner JC and Sinnis P

Cellular microbiology 2016

PUBMED: 27084458; DOI: 10.1111/cmi.12601
Calcium signalling in malaria parasites.

Brochet M and Billker O

Molecular microbiology 2016

PUBMED: 26748879; DOI: 10.1111/mmi.13324
A Stem Cell Strategy Identifies Glycophorin C as a Major Erythrocyte Receptor for the Rodent Malaria Parasite Plasmodium berghei.

Yiangou L, Montandon R, Modrzynska K, Rosen B, Bushell W et al.

PloS one 2016;11;6;e0158238

PUBMED: 27362409; PMC: 4928779; DOI: 10.1371/journal.pone.0158238
Enhanced Methylation Analysis by Recovery of Unsequenceable Fragments.

McInroy GR, Beraldi D, Raiber EA, Modrzynska K, van Delft P et al.

PloS one 2016;11;3;e0152322

PUBMED: 27031619; PMC: 4816320; DOI: 10.1371/journal.pone.0152322

The Kinomics of Malaria

BROCHET, M., Tobin, A.B., BILLKER et al.

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
Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.

Chertow JH, Alkaitis MS, Nardone G, Ikeda AK, Cunnington AJ et al.

PLoS pathogens 2015;11;9;e1005119

PUBMED: 26407009; PMC: 4583463; DOI: 10.1371/journal.ppat.1005119
Calcium Builds Strong Host-Parasite Interactions.

Billker O and Rayner JC

Cell host & microbe 2015;18;1;9-10

PUBMED: 26159715; DOI: 10.1016/j.chom.2015.06.012
A genome-scale vector resource enables high-throughput reverse genetic screening in a malaria parasite.

Gomes AR, Bushell E, Schwach F, Girling G, Anar B et al.

Cell host & microbe 2015;17;3;404-413

PUBMED: 25732065; PMC: 4362957; DOI: 10.1016/j.chom.2015.01.014
Conditional-ready mouse embryonic stem cell derived macrophages enable the study of essential genes in macrophage function.

Yeung AT, Hale C, Xia J, Tate PH, Goulding D et al.

Scientific reports 2015;5;8908

PUBMED: 25752829; PMC: 4354151; DOI: 10.1038/srep08908
PlasmoGEM, a database supporting a community resource for large-scale experimental genetics in malaria parasites.

Schwach F, Bushell E, Gomes AR, Anar B, Girling G et al.

Nucleic acids research 2015;43;Database issue;D1176-82

PUBMED: 25593348; PMC: 4383951; DOI: 10.1093/nar/gku1143

A comprehensive evaluation of rodent malaria parasite genomes and gene expression.

Otto TD, Böhme U, Jackson AP, Hunt M, Franke-Fayard B et al.

BMC biology 2014;12;86

PUBMED: 25359557; PMC: 4242472; DOI: 10.1186/s12915-014-0086-0
BCKDH: the missing link in apicomplexan mitochondrial metabolism is required for full virulence of Toxoplasma gondii and Plasmodium berghei.

Oppenheim RD, Creek DJ, Macrae JI, Modrzynska KK, Pino P et al.

PLoS pathogens 2014;10;7;e1004263

PUBMED: 25032958; PMC: 4102578; DOI: 10.1371/journal.ppat.1004263
A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium.

Sinha A, Hughes KR, Modrzynska KK, Otto TD, Pfander C et al.

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.

Brochet M, Collins MO, Smith TK, Thompson E, Sebastian S et al.

PLoS biology 2014;12;3;e1001806

PUBMED: 24594931; PMC: 3942320; DOI: 10.1371/journal.pbio.1001806
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.

Bauza K, Malinauskas T, Pfander C, Anar B, Jones EY et al.

Infection and immunity 2014;82;3;1277-86

PUBMED: 24379295; PMC: 3957994; DOI: 10.1128/IAI.01187-13

Global analysis of apicomplexan protein S-acyl transferases reveals an enzyme essential for invasion.

Frénal K, Tay CL, Mueller C, Bushell ES, Jia Y et al.

Traffic (Copenhagen, Denmark) 2013;14;8;895-911

PUBMED: 23638681; PMC: 3813974; DOI: 10.1111/tra.12081
Comparative genomics in Chlamydomonas and Plasmodium identifies an ancient nuclear envelope protein family essential for sexual reproduction in protists, fungi, plants, and vertebrates.

Ning J, Otto TD, Pfander C, Schwach F, Brochet M et al.

Genes & development 2013;27;10;1198-215

PUBMED: 23699412; PMC: 3672651; DOI: 10.1101/gad.212746.112
Defining the range of pathogens susceptible to Ifitm3 restriction using a knockout mouse model.

Everitt AR, Clare S, McDonald JU, Kane L, Harcourt K et al.

PloS one 2013;8;11;e80723

PUBMED: 24278312; PMC: 3836756; DOI: 10.1371/journal.pone.0080723

A tetracycline-repressible transactivator system to study essential genes in malaria parasites.

Pino P, Sebastian S, Kim EA, Bush E, Brochet M et al.

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.

Sebastian S, Brochet M, Collins MO, Schwach F, Jones ML et al.

Cell host & microbe 2012;12;1;9-19

PUBMED: 22817984; PMC: 3414820; DOI: 10.1016/j.chom.2012.05.014
Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors.

Ojo KK, Pfander C, Mueller NR, Burstroem C, Larson ET et al.

The Journal of clinical investigation 2012;122;6;2301-5

PUBMED: 22565309; PMC: 3366411; DOI: 10.1172/JCI61822

A scalable pipeline for highly effective genetic modification of a malaria parasite.

Pfander C, Anar B, Schwach F, Otto TD, Brochet M et al.

Nature methods 2011;8;12;1078-82

PUBMED: 22020067; PMC: 3431185; DOI: 10.1038/nmeth.1742
Genetic and transcriptional analysis of phosphoinositide-specific phospholipase C in Plasmodium.

Raabe A, Berry L, Sollelis L, Cerdan R, Tawk L et al.

Experimental parasitology 2011;129;1;75-80

PUBMED: 21651909; DOI: 10.1016/j.exppara.2011.05.023
Multiple roles for Plasmodium berghei phosphoinositide-specific phospholipase C in regulating gametocyte activation and differentiation.

Raabe AC, Wengelnik K, Billker O and Vial HJ

Cellular microbiology 2011;13;7;955-66

PUBMED: 21518218; PMC: 3132445; DOI: 10.1111/j.1462-5822.2011.01591.x
Cutting edge: the membrane attack complex of complement is required for the development of murine experimental cerebral malaria.

Ramos TN, Darley MM, Hu X, Billker O, Rayner JC et al.

Journal of immunology (Baltimore, Md. : 1950) 2011;186;12;6657-60

PUBMED: 21572031; PMC: 3110530; DOI: 10.4049/jimmunol.1100603

The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission.

Tewari R, Straschil U, Bateman A, Böhme U, Cherevach I et al.

Cell host & microbe 2010;8;4;377-87

PUBMED: 20951971; PMC: 2977076; DOI: 10.1016/j.chom.2010.09.006
A parasite calcium switch and Achilles' heel revealed.

Doerig C and Billker O

Nature structural & molecular biology 2010;17;5;541-3

PUBMED: 20442739; DOI: 10.1038/nsmb0510-541

Quantitative assessment of DNA replication to monitor microgametogenesis in Plasmodium berghei.

Raabe AC, Billker O, Vial HJ and Wengelnik K

Molecular and biochemical parasitology 2009;168;2;172-6

PUBMED: 19712704; PMC: 2789244; DOI: 10.1016/j.molbiopara.2009.08.004
A cyclic GMP signalling module that regulates gliding motility in a malaria parasite.

Moon RW, Taylor CJ, Bex C, Schepers R, Goulding D et al.

PLoS pathogens 2009;5;9;e1000599

PUBMED: 19779564; PMC: 2742896; DOI: 10.1371/journal.ppat.1000599
Signalling in malaria parasites. The MALSIG consortium.

Doerig C, Baker D, Billker O, Blackman MJ, Chitnis C et al.

Parasite (Paris, France) 2009;16;3;169-82

PUBMED: 19839262
An essential role for the Plasmodium Nek-2 Nima-related protein kinase in the sexual development of malaria parasites.

Reininger L, Tewari R, Fennell C, Holland Z, Goldring D et al.

The Journal of biological chemistry 2009;284;31;20858-68

PUBMED: 19491095; PMC: 2742851; DOI: 10.1074/jbc.M109.017988
Calcium-dependent signaling and kinases in apicomplexan parasites.

Billker O, Lourido S and Sibley LD

Cell host & microbe 2009;5;6;612-22

PUBMED: 19527888; PMC: 2718762; DOI: 10.1016/j.chom.2009.05.017

Protein kinases of malaria parasites: an update.

Doerig C, Billker O, Haystead T, Sharma P, Tobin AB and Waters NC

Trends in parasitology 2008;24;12;570-7

PUBMED: 18845480; DOI: 10.1016/j.pt.2008.08.007
Gametogenesis in malaria parasites is mediated by the cGMP-dependent protein kinase.

McRobert L, Taylor CJ, Deng W, Fivelman QL, Cummings RM et al.

PLoS biology 2008;6;6;e139

PUBMED: 18532880; PMC: 2408617; DOI: 10.1371/journal.pbio.0060139
The conserved plant sterility gene HAP2 functions after attachment of fusogenic membranes in Chlamydomonas and Plasmodium gametes.

Liu Y, Tewari R, Ning J, Blagborough AM, Garbom S et al.

Genes & development 2008;22;8;1051-68

PUBMED: 18367645; PMC: 2335326; DOI: 10.1101/gad.1656508

Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade host cells.

Coppi A, Tewari R, Bishop JR, Bennett BL, Lawrence R et al.

Cell host & microbe 2007;2;5;316-27

PUBMED: 18005753; PMC: 2117360; DOI: 10.1016/j.chom.2007.10.002

Plasmodium berghei calcium-dependent protein kinase 3 is required for ookinete gliding motility and mosquito midgut invasion.

Siden-Kiamos I, Ecker A, Nybäck S, Louis C, Sinden RE and Billker O

Molecular microbiology 2006;60;6;1355-63

PUBMED: 16796674; PMC: 1513514; DOI: 10.1111/j.1365-2958.2006.05189.x
Generation of gene targeting constructs for Plasmodium berghei by a PCR-based method amenable to high throughput applications.

Ecker A, Moon R, Sinden RE and Billker O

Molecular and biochemical parasitology 2006;145;2;265-8

PUBMED: 16290088; DOI: 10.1016/j.molbiopara.2005.10.006

Protein kinases as targets for antimalarial intervention: Kinomics, structure-based design, transmission-blockade, and targeting host cell enzymes.

Doerig C, Billker O, Pratt D and Endicott J

Biochimica et biophysica acta 2005;1754;1-2;132-50

PUBMED: 16271522; DOI: 10.1016/j.bbapap.2005.08.027
An atypical mitogen-activated protein kinase controls cytokinesis and flagellar motility during male gamete formation in a malaria parasite.

Tewari R, Dorin D, Moon R, Doerig C and Billker O

Molecular microbiology 2005;58;5;1253-63

PUBMED: 16313614; DOI: 10.1111/j.1365-2958.2005.04793.x
A NIMA-related protein kinase is essential for completion of the sexual cycle of malaria parasites.

Reininger L, Billker O, Tewari R, Mukhopadhyay A, Fennell C et al.

The Journal of biological chemistry 2005;280;36;31957-64

PUBMED: 15970588; DOI: 10.1074/jbc.M504523200

Calcium and a calcium-dependent protein kinase regulate gamete formation and mosquito transmission in a malaria parasite.

Billker O, Dechamps S, Tewari R, Wenig G, Franke-Fayard B and Brinkmann V

Cell 2004;117;4;503-14

PUBMED: 15137943
Differential recognition of members of the carcinoembryonic antigen family by Afa/Dr adhesins of diffusely adhering Escherichia coli (Afa/Dr DAEC).

Berger CN, Billker O, Meyer TF, Servin AL and Kansau I

Molecular microbiology 2004;52;4;963-83

PUBMED: 15130118; DOI: 10.1111/j.1365-2958.2004.04033.x

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.

Alavi Y, Arai M, Mendoza J, Tufet-Bayona M, Sinha R et al.

International journal for parasitology 2003;33;9;933-43

PUBMED: 12906877

Azadirachtin disrupts formation of organised microtubule arrays during microgametogenesis of Plasmodium berghei.

Billker O, Shaw MK, Jones IW, Ley SV, Mordue AJ and Sinden RE

The Journal of eukaryotic microbiology 2002;49;6;489-97

PUBMED: 12503686
Nuclear factor-kappa B directs carcinoembryonic antigen-related cellular adhesion molecule 1 receptor expression in Neisseria gonorrhoeae-infected epithelial cells.

Muenzner P, Billker O, Meyer TF and Naumann M

The Journal of biological chemistry 2002;277;9;7438-46

PUBMED: 11751883; DOI: 10.1074/jbc.M108135200
Distinct mechanisms of internalization of Neisseria gonorrhoeae by members of the CEACAM receptor family involving Rac1- and Cdc42-dependent and -independent pathways.

Billker O, Popp A, Brinkmann V, Wenig G, Schneider J et al.

The EMBO journal 2002;21;4;560-71

PUBMED: 11847104; PMC: 125849

Signal transduction pathways induced by virulence factors of Neisseria gonorrhoeae.

Popp A, Billker O and Rudel T

International journal of medical microbiology : IJMM 2001;291;4;307-14

PUBMED: 11680791; DOI: 10.1078/1438-4221-00134
Both mosquito-derived xanthurenic acid and a host blood-derived factor regulate gametogenesis of Plasmodium in the midgut of the mosquito.

Arai M, Billker O, Morris HR, Panico M, Delcroix M et al.

Molecular and biochemical parasitology 2001;116;1;17-24

PUBMED: 11463462

The structural basis of CEACAM-receptor targeting by neisserial Opa proteins.

Billker O, Popp A, Gray-Owen SD and Meyer TF

Trends in microbiology 2000;8;6;258-60; discussion 260-1

PUBMED: 10838580
Determination of mosquito bloodmeal pH in situ by ion-selective microelectrode measurement: implications for the regulation of malarial gametogenesis.

Billker O, Miller AJ and Sinden RE

Parasitology 2000;120 ( Pt 6);547-51

PUBMED: 10874717

Identification of xanthurenic acid as the putative inducer of malaria development in the mosquito.

Billker O, Lindo V, Panico M, Etienne AE, Paxton T et al.

Nature 1998;392;6673;289-92

PUBMED: 9521324; DOI: 10.1038/32667

Billker Group | Rodent models of malaria

Billker Group | Rodent models of malaria

Billker Group

Our Research and Approach

Tools and resources for P. berghei genetic modification.

Signal Transduction Pathways Regulating Sexual Development

Host Genes Regulating Parasite Development

People

Group Leader

Bronner-Anar, Burcu

Bushell, Ellen

Girling, Gareth

Montandon, Ruddy

Muraro, Daniele

Raddi, Gianmarco

Russell, Andrew J C

Schwach, Frank

Alumni

Marsden, Sarah

Key Projects, Collaborations, Tools & Data

Research Programmes

Partners and Funders

Internal Partners

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

A comprehensive evaluation of rodent malaria parasite genomes and gene expression.

Phosphoinositide metabolism links cGMP-dependent protein kinase G to essential Ca²⁺ signals at key decision points in the life cycle of malaria parasites.

A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium.

Comparative genomics in Chlamydomonas and Plasmodium identifies an ancient nuclear envelope protein family essential for sexual reproduction in protists, fungi, plants, and vertebrates.

A tetracycline-repressible transactivator system to study essential genes in malaria parasites.

A Plasmodium calcium-dependent protein kinase controls zygote development and transmission by translationally activating repressed mRNAs.

A scalable pipeline for highly effective genetic modification of a malaria parasite.

The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission.

The conserved plant sterility gene HAP2 functions after attachment of fusogenic membranes in Chlamydomonas and Plasmodium gametes.

Calcium and a calcium-dependent protein kinase regulate gamete formation and mosquito transmission in a malaria parasite.

Distinct mechanisms of internalization of Neisseria gonorrhoeae by members of the CEACAM receptor family involving Rac1- and Cdc42-dependent and -independent pathways.

Identification of xanthurenic acid as the putative inducer of malaria development in the mosquito.

Alpha-v-containing integrins are host receptors for the <i>Plasmodium falciparum</i> sporozoite surface protein, TRAP.

Complete avian malaria parasite genomes reveal features associated with lineage-specific evolution in birds and mammals.

Single-cell RNA-seq reveals hidden transcriptional variation in malaria parasites.

Sub-minute Phosphoregulation of Cell Cycle Systems during Plasmodium Gamete Formation.

Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes.

Nutrient sensing modulates malaria parasite virulence.

Proteomic profiling of the brain of mice with experimental cerebral malaria.

Single-cell RNA-seq and computational analysis using temporal mixture modelling resolves Th1/Tfh fate bifurcation in malaria.

Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria.

Invasion of hepatocytes by Plasmodium sporozoites requires cGMP-dependent protein kinase and calcium dependent protein kinase 4.

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

Calcium signalling in malaria parasites.

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

Enhanced Methylation Analysis by Recovery of Unsequenceable Fragments.

The Kinomics of Malaria

Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.

Calcium Builds Strong Host-Parasite Interactions.

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

Conditional-ready mouse embryonic stem cell derived macrophages enable the study of essential genes in macrophage function.

PlasmoGEM, a database supporting a community resource for large-scale experimental genetics in malaria parasites.

A comprehensive evaluation of rodent malaria parasite genomes and gene expression.

BCKDH: the missing link in apicomplexan mitochondrial metabolism is required for full virulence of Toxoplasma gondii and Plasmodium berghei.

A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium.

Phosphoinositide metabolism links cGMP-dependent protein kinase G to essential Ca²⁺ signals at key decision points in the life cycle of malaria parasites.

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.

Global analysis of apicomplexan protein S-acyl transferases reveals an enzyme essential for invasion.

Comparative genomics in Chlamydomonas and Plasmodium identifies an ancient nuclear envelope protein family essential for sexual reproduction in protists, fungi, plants, and vertebrates.

Defining the range of pathogens susceptible to Ifitm3 restriction using a knockout mouse model.

A tetracycline-repressible transactivator system to study essential genes in malaria parasites.

A Plasmodium calcium-dependent protein kinase controls zygote development and transmission by translationally activating repressed mRNAs.

Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors.

A scalable pipeline for highly effective genetic modification of a malaria parasite.

Genetic and transcriptional analysis of phosphoinositide-specific phospholipase C in Plasmodium.

Multiple roles for Plasmodium berghei phosphoinositide-specific phospholipase C in regulating gametocyte activation and differentiation.

Cutting edge: the membrane attack complex of complement is required for the development of murine experimental cerebral malaria.

The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission.

A parasite calcium switch and Achilles' heel revealed.

Quantitative assessment of DNA replication to monitor microgametogenesis in Plasmodium berghei.

A cyclic GMP signalling module that regulates gliding motility in a malaria parasite.

Signalling in malaria parasites. The MALSIG consortium.

An essential role for the Plasmodium Nek-2 Nima-related protein kinase in the sexual development of malaria parasites.

Calcium-dependent signaling and kinases in apicomplexan parasites.

Protein kinases of malaria parasites: an update.