London School of Hygiene & Tropical Medicine

Researchers at the London School of Hygiene & Tropical Medicine and the Medical Research Council (MRC) Toxicology Unit based at the University of Leicester have demonstrated the molecular workings of a vital parasite signalling protein called protein kinase G (PKG). PKG is needed for malaria parasites to survive, both in the blood of infected people and in the mosquitoes that transmit malaria.

Their findings reveal PKG could be an excellent drug target in both the treatment of malaria and in blocking its transmission to mosquitoes.

Professor David Baker, co-lead author from the London School of Hygiene & Tropical Medicine, said: "It is a great advantage in drug discovery research if you know the identity of the molecular target of a particular drug and the consequences of blocking its function. It helps in designing the most effective combination treatments, and to avoid drug resistance which is a major problem in the control of malaria worldwide."

Malaria causes more than half a million deaths per year, mostly among African children. The malaria parasite exists in two main forms that make up its life cycle in the human and mosquito hosts.

The first stage lives in the blood stream of an infected person and causes the clinical symptoms of malaria, including the characteristic fever as millions of parasites all burst out of red blood cells simultaneously.

The second form of the parasite does not cause symptoms, but is crucial for the transmission of malaria by mosquitoes as it undergoes sexual reproduction inside the insect after having been ingested during a blood meal, completing the parasite's life cycle.

Previous work in Professor Baker's lab at the School has shown that PKG has an essential role in both the blood stages and the mosquito stages of the parasite life cycle. In both cases his team found that PKG allows malaria parasites to escape from red blood cells. They escape either into the blood stream to colonise new red blood cells to perpetuate the disease, or into the mosquito stomach immediately after a blood meal to allow continuation of the cycle and transmission of malaria to other people.

Development of a drug which targets PKG would therefore cure patients suffering from malaria and also block transmission of the disease by mosquitoes.

The researchers used state-of-the-art technology to dissect the biochemical pathway that PKG controls in the blood stages of the malaria parasite. This allowed the scientists to discover exactly which parasite proteins are activated by PKG via phosphorylation. The work delivered exciting new knowledge on how this pathway works and how this protein triggers the parasite to escape from human red blood cells.

The study was funded by the Wellcome Trust and the MRC.

Video: Killing the malaria parasite, University of Leicester

Publication:

• Mahmood M. Alam,Lev Solyakov, Andrew R. Bottrill, Christian Flueck, Faiza A. Siddiqui, Shailja Singh, Sharad Mistry, Maria Viskaduraki, Kate Lee, Christine S. Hopp, Chetan E. Chitnis, Christian Doerig, Robert W. Moon, Judith L. Green, Anthony A. Holder, David A. Baker & Andrew B. Tobin. Phosphoproteomics reveals malaria parasite Protein Kinase G as a signalling hub regulating egress and invasion. Nature Communications. DOI: 10.1038/ncomms8285

Related links:

• Malaria Centre