Billker Group | Rodent models of malaria

Billker Group | Rodent models of malaria

Billker Group

Billker GroupSanger 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.

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People

Billker, Oliver
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

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;404-13

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • Calcium signalling in malaria parasites.

    Brochet M and Billker O

    Molecular microbiology 2016

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • A parasite calcium switch and Achilles' heel revealed.

    Doerig C and Billker O

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

  • 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

  • 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

  • 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

  • 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

  • Calcium-dependent signaling and kinases in apicomplexan parasites.

    Billker O, Lourido S and Sibley LD

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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • The roles of temperature, pH and mosquito factors as triggers of male and female gametogenesis of Plasmodium berghei in vitro.

    Billker O, Shaw MK, Margos G and Sinden RE

    Parasitology 1997;115 ( Pt 1);1-7