Malaria programme: Billker group

The aims of the Billker group in the Sanger Malaria programme are to elucidate the fundamental molecular and cell biology of malaria parasites with a view to understanding their development and transmission.

The team studies the malaria species that infects rodents, Plasmodium berghei, which is harmless to humans. This species is easy to maintain throughout its life cycle in the laboratory. Genome sequences are available for parasite, host and vector and all three organisms can be manipulated genetically. Rodent malaria parasites therefore offer a powerful experimental model to study fundamental aspects of malaria biology, pathology, immunology and antimalarial drug action. The team is investigating how the genome sequence functions in malaria parasites and in parasite-host interactions, with a view to aiding the development of more effective antimalarial drugs.

[Wellcome Library, London]

Background

Malaria kills between one and two million people annually. The development of new drugs and vaccines poses one of the major challenges to current medical research, and 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 (vectors).

A group of proteins called protein kinases are important regulators of parasite behaviour and life cycle progression. The genomes of different Plasmodium species encode between 65 and 85 typical protein kinases. The systematic functional analysis of kinase genes in P. berghei has begun to reveal key proteins that affect the development of the parasite in the mosquito. This functional analysis is achieved by disrupting a gene and seeing the effect this has on the organism. Many kinase genes cannot be disrupted, however, probably because the proteins they encode are essential for the parasite. To identify the functions of these essential kinases is therefore a major challenge, but the results will lead to the best drug targets in the kinase family.

Research

Our aims

The Billker group is seeking to understand basic principles of molecular signalling cascades called signal transduction pathways, involving protein kinases, that regulate the malaria life cycle, and to identify key molecular interactions that determine host and vector susceptibility.

Resources

Our approach

We are developing new genetic tools for the large scale analysis of gene function in the rodent malaria parasite, P. berghei. We also aim to contribute to the Mouse Genetics Programme by identifying host genes affecting malaria susceptibility and pathology.

Selected Publications

  • 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, Pei J, Grishin NV, Steele RE, Sinden RE, Snell WJ and Billker O

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

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

  • 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, Esko JD, Billker O and Sinnis P

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

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

  • 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

  • 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

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

    Billker O, Lindo V, Panico M, Etienne AE, Paxton T, Dell A, Rogers M, Sinden RE and Morris HR

    Nature 1998;392;6673;289-92

    PUBMED: 9521324; DOI: 10.1038/32667