Tony Holder

Malaria Parasitology Laboratory

Malaria is caused by a parasitic protozoan that invades red blood cells, where it develops and multiplies before bursting out and invading new red cells. This cycle is responsible for the disease. There is much interest in understanding the interaction between the parasite and the host immune system, to contribute to the development of a malaria vaccine. The identification of new targets for drugs to kill the parasite and interrupt the cycle of multiplication offers the potential of much needed new therapeutic interventions.

In one project, focused on how the parasite invades host cells, we study the actomyosin-based motor that drives invasion. We have shown that an unusual calcium-dependent protein kinase phosphorylates two of the proteins in the motor complex, a process that may be important in its assembly. Together with colleagues at MRC Technology we have identified chemical compounds that inhibit this kinase and kill the parasite at very low concentrations. These compounds have the potential to be developed into drugs against malaria and are powerful reagents to dissect the exact role of this kinase in the parasite's biology.

Figure 1

Within the parasite's cycle of invasion and development we study several aspects of its cell biology and biochemistry to understand the complex interaction between parasite and host. (Click to view larger image)

Figure 2

Location of an apical rhoptry protein (RhopH2), an invasion motor protein (GAP45) and a surface protein (MSP1) in merozoites within a schizont. (Click to view larger image)

Selected publications

Curd, RD; Birdsall, B; Kadekoppala, M; Ogun, SA; Kelly, G and Holder, AA (2014) The structure of Plasmodium yoelii merozoite surface protein 119, antibody specificity and implications for malaria vaccine design.** Open Biology 4, 130091

Wright, MH; Clough, B; Rackham, MD; Rangachari, K; Brannigan, JA; Grainger, M; Moss, DK; Bottrill, AR; Heal, WP; Broncel, M; Serwa, RA; Brady, D; Mann, DJ; Leatherbarrow, RJ; Tewari, R; Wilkinson, AJ; Holder, AA and Tate, EW (2014) Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach. Nature Chemistry  6 112-121

Moon, RW; Hall, J; Rangkuti, F; Ho, YS; Almond, N; Mitchell, GH; Pain, A; Holder, AA and Blackman, MJ (2012) Adaptation of the genetically tractable malaria pathogen Plasmodium knowlesi to continuous culture in human erythrocytes. Proceedings of the National Academy of Sciences 110, 531-536

Tony Holder

tony.holder@crick.ac.uk
+44 (0)20 379 62332

  • 1972-1975 PhD Genetics, University of Leeds, UK
  • 1975-1978 Postdoctoral fellow, The Carlsberg Laboratory, Copenhagen, Denmark
  • 1978-1988 Senior Scientist, The Wellcome Research Laboratories, Beckenham, UK
  • 1988-2015 Head, Division of Parasitology, MRC-NIMR, Mill Hill, UK
  • 2015 Group Leader, the Francis Crick Institute, London, UK