Published the 20/09/2012 in Press Releases

Enzyme discovery may lead to new ways to fight malaria

Scientists have discovered a unique enzyme that is a key player in enabling the malaria parasite to invade mosquitoes, raising hopes that the discovery could eventually lead to new strategies to prevent the spread of this deadly disease.

The work was a collaborative effort by scientists at the MRC's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute) and colleagues from the Universities of Nottingham, Oxford, Edinburgh, Leicester and Imperial College London.

Malaria is caused by five species of Plasmodium protozoan parasites. The parasites are spread to people through the bites of infected Anopheles mosquitoes.

First, a mosquito bites an infected person and takes a blood meal that contains malarial 'sperm' and egg precursor cells. Following fertilisation, a motile 'ookinete' is formed - this is the fertilised form of the malaria parasite, which is able to move spontaneously. This ookinete burrows through the mosquito's gut wall and comes to rest on the other side. Here it turns into an 'oocyst' - a thick-walled structure that produces thousands of infective 'sporozoites'. These cells are the form of the parasite that infects new human hosts - the sporozoites migrate to the mosquito's salivary glands and are transmitted when the mosquito bites its next victim.

In the current research, the scientists discovered a unique enzyme called PPKL. It belongs to a family of proteins found only in bacteria, plants and algae and some protozoa, such as the malaria parasite. PPKL is a type of enzyme known as a protein phosphatase - which removes phosphate groups from proteins to control their functions. PPKL is mostly found in female gametocytes (the precursors to female egg cells) and ookinetes.

Studying the malaria parasite in the lab, the researchers deleted the gene that contains the instructions for the parasite to make PPKL. This caused abnormal ookinete development, including loss of movement - which meant that the parasite could no longer cross the mosquito gut wall, effectively stopping the spread of infection.

By deleting the gene for PPKL, the ookinete (the fertilised form of the malaria parasite) has a grossly abnormal shape and is no longer able to move spontaneously.

"Transmission through the mosquito represents a bottleneck in the parasite's life cycle. Therapeutic strategies to target these stages will be essential to the long term goal to eradicate and finally eliminate malaria," explained Tony Holder of NIMR.

Rita Tewari, of the University of Nottingham, added: "This is the first step in understanding the functional role of phosphatases in malaria biology. Although they have many different functions, they can be explored as good targets for malaria control. The control of parasite transmission is important in order to prevent the spread of malaria and targeting PPKL could be an important player in this process."

Paper: A Unique Protein Phosphatase with Kelch-Like Domains (PPKL) in Plasmodium Modulates Ookinete Differentiation, Motility and Invasion .

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