Malaria parasites and red blood cells

Lead Research Organisation: The Francis Crick Institute

Abstract

Malaria remains a significant disease worldwide and there is a need for new therapeutics, for examples a vaccine or new drugs, to complement existing control and treatment strategies. Our starting point is to understand the biology of the parasite that causes malaria and then use that understanding to identify key processes that are essential for parasite growth and multiplication as targets for the development and assessment of potential new therapeutics. For example, we defined and characterized extensively a candidate vaccine component on the surface of the parasite and have driven two drug discovery programmes focused on enzyme targets within the cell. We will continue to explore unique aspects of the parasite’s cycle of development, at the stage of its life cycle that is responsible for the disease, to provide insights into areas for further intervention; this is particularly important at a time when there is growing evidence of parasite resistance to widely-used front line antimalarial drugs.

Technical Summary

This work was supported by the Francis Crick Institute which receives its core funding from the UK Medical Research Council (FC001000), the Wellcome Trust (FC001000),and Cancer Research UK (FC001000)

Malaria remains the single most important infectious cause of mortality in children under the age of five worldwide. In endemic areas, malaria mortality and morbidity in all age groups have extensive impact on provision of health care resources and economic activity. Current malaria control activities are focused around use of insecticide-impregnated bed nets to reduce mosquito-mediated transmission, and the treatment of clinical infections, for example with artemisin-based combination therapies. New medicines are needed to counter the evolution and spread of drug resistant parasites and further tools for intervention including effective vaccines are also required. The disease is caused by the asexual blood stage of the parasite’s life cycle with the parasite invading host red blood cells, where mitosis produces a multinucleate schizont and subsequent cytokinesis results in the formation and release of extracellular merozoites, which go on to invade fresh red blood cells. This cycle of a ~30-fold replication every 48 hours in the case of Plasmodium falciparum has been my primary area of research, with substantial contributions to our understanding of the host-parasite interface such as erythrocyte invasion, which underpins vaccine development, and an exploration of aspects of protein post-translational modification, which has identified targets for new drug discovery and development.
Our current research is focused on the role of merozoite surface proteins and parasite actomyosin motors in erythrocyte invasion, and on protein N-myristoylation and ubiquitylation in parasite biology. We use a combination of genetics, biochemistry and cell biology together with chemical biology approaches to address these issues. We have recently established in the lab CRISPR-based and inducible gene knockout genetic strategies, and these approaches have enhanced our ability to analyse gene function. We are identifying N-myristoyl transferase (NMT) substrates and carrying out a detailed analysis of the parasite ubiquitome during intra- and extracellular developmental stages. Together with Tate (Imperial) and Pharma collaborators we are developing small molecule inhibitors and specific probes to dissect enzyme function in parasite biology and to explore potential avenues for drug discovery. From our previous work this has led to both NMT and calcium-dependent protein kinase 1 inhibitors being progressed for evaluation as lead compounds by Medicines for Malaria Venture. We are currently examining the potential of ubiquitin activating enzyme as a potential malaria drug target. We will continue to collaborate with Tewari (Nottingham) on aspects of the cell cycle, including the role of inner membrane complex formation in cytokinesis, with Molloy (Crick) on actin-myosin biophysics, and with Lasonder (Plymouth) on bioinformatic analysis of proteome data.
In the future we will continue with these research themes although with reduced emphasis on erythrocyte invasion and greater focus on protein modification and its role in parasite biology. This will underpin further studies on novel target validation and drug discovery.

Publications

10 25 50