Breakthrough in the battle against malaria

An international team of scientists has announced a breakthrough in the fight against malaria, paving the way for the development of new drugs to treat the deadly disease.

According to the World Health Organisation malaria currently infects more then 225 million people worldwide and accounts for nearly 800,000 deaths per year. Most deaths occur among children living in Africa where a child dies every 45 seconds of malaria and the disease accounts for approximately 20% of all childhood deaths. The disease is caused by the malaria parasite, Plasmodium, that is injected into the human host through the bite of the female Anopheles mosquito.

Now researchers have discovered new ways in which the malarial parasite survives in the bloodstream of its victims.

The advance is the result of a collaboration between medical scientists at the University of Leicester in the UK and a team from the French Institut National de la Santé et de la Recherche Médicale (Inserm) working at the Wellcome Trust Centre for Molecular Parasitology in Glasgow and the Ecole Polytechnique Fédérale de Lausanne (EPFL, Switzerland), now relocating to Monash University in Melbourne (Australia).

The breakthrough was made by the teams led by Professor Andrew Tobin at the University of Leicester and Professor Christian Doerig, now at Monash University, and is published in the prestigious scientific journal Nature Communications and was funded by The Wellcome Trust, the European Commission, Inserm and EPFL.

Professor Tobin, of the Department of Cell Physiology and Pharmacology, said: "I am proud to be involved in a collaboration that has made such an impact on malaria research. Our study opens new avenues for researchers to look for new drugs that treat malaria."

Professor Doerig explained "We have shown that a crucial element that is required by malaria parasites to survive in the human blood stream is a group of enzymes called protein kinases. If we stop these proteins kinases from working then we kill the malaria parasites. We are now looking for drugs that do exactly that – stop the protein kinases from working. If we find these drugs then we will have a new way of killing the malaria parasite."

Professor Tobin added: "It seems perfectly realistic to us that we can now develop novel anti-malaria drugs based on the findings that we have made – it certainly is a big moment in our fight against this terrible disease that mainly affects the world's poorest people."

Tobin and Doerig also warn: "The parasite is very clever at adapting to drug treatments and in so doing becoming resistant to drugs. In fact, there is already evidence that the parasite is developing resistance to the most recent front line treatment for malaria.

"To avoid the catastrophic affects of widespread resistance to anti-malarial treatments we need a continued pipeline of new anti-malaria drugs. Our discovery provides one avenue towards populating such a pipeline."

Notes to newsdesk:

For more information, please contact the Corresponding Authors who contributed equally to the study:

Andrew B. Tobin, University of Leicester: Tel: +44116 2522935, e-mail: tba@le.ac.uk;

Christian Doerig: Tel: +61 3 990 29138, Fax: +61 3 990 29222, e-mail: Christian.doerig@monash.edu

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk

Details of the paper: The full listing of authors and their affiliations for this paper is as follows:

Lev Solyakov1,*, Jean Halbert2,3,*, Mahmood M. Alam1,*, Jean-Philippe Semblat2,3, Dominique Dorin-Semblat2,3, Luc Reininger2,3, Andrew R. Bottrill4, Sharad Mistry4, Abdirhaman Abdi2,3, Clare Fennell3, Zoe Holland3, Claudia Demarta2, Yvan Bouza2, Audrey Sicard2,3, Marie-Paule Nivez3, Sylvain Eschenlauer3, Tenzing Lama2, Divya Catherine Thomas5, Pushkar Sharma5, Shruti Agarwal6, Selina Kern6, Gabriele Pradel6, Michele Graciotti1, Andrew B. Tobin1 & Christian Doerig2,3,7

1 Department of Cell Physiology and Pharmacology, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.

2 Inserm-EPFL Joint Laboratory, Global Health Institute, EPFL-SV-GHI, Station 19, Lausanne CH-1015, Switzerland.

3 Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow G12 8TA, UK.

4 Protein and Nucleic Acid Chemistry Laboratory, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.

5 EGE Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.

6 Research Center for Infectious Diseases, University of Würzburg, Josef-Schneider-Strasse 2/D15, Würzburg 97080, Germany.

7 Department of Microbiology, Building 76, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.

The following funding acknowledgements from the authors appear at the end of the paper:

This work was supported by a joint project award from the Wellcome Trust to AT and CD (090313). Work in the CD laboratory was also supported by Inserm, EPFL, the FP6 (SIGMAL and ANTIMAL projects, BioMalPar Network of Excellence) and FP7 (MALSIG project and EviMalar network of Excellence) programmes of the European Commission. AA benefited from a PhD studentship from the international PhD programme of the FP6 ANTIMAL Integrated Project, JH from a studentship from the French Ministère de la Défense (Délégation Générale pour l'Armement (DGA)), and CF and ZH from PhD studentships awarded by the Wellcome Trust.

Nature Communications is an online only journal. The online version of the article can be considered definitive. These papers will be citable via a digital object identifier (DOI) number. The DOI for this paper will be 10.1038/ncomms1558. Once the paper is published electronically, the DOI can be used to retrieve the paper by adding it to the following URL: http://dx.doi.org/

Abstract

The role of protein phosphorylation in the life cycle of malaria parasites is only slowly emerging. Here we combine global phospho-proteomic analysis with kinome-wide reverse genetics to assess the importance of protein phosphorylation in Plasmodium falciparum asexual proliferation. We identify 1177 phosphorylation sites on 650 parasite proteins that are involved in a wide range of general cellular activity such as DNA synthesis, transcription and metabolism as well as key parasite processes such as invasion and cyto-adherence. Several parasite protein kinases are themselves phosphorylated on putative regulatory residues, including tyrosines in the activation loop of PfGSK3 (PFC0525c) and PfCLK3 (PF11_0156); we show that phosphorylation of PfCLK3 Y526 is essential for full kinase activity. A kinome-wide reverse genetics strategy identified 36 parasite kinases as likely essential for erythrocytic schizogony. These studies not only reveal processes that are regulated by protein phosphorylation, but also define potential anti-malarial drug targets within the parasite kinome.

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