Dissecting the Red Blood Cell invasion pathways of the Malaria parasite Plasmodium knowlesi
The objectives of this project are to:
- Unravel the process of red blood cell (RBC) invasion by malaria parasites, an important target for novel drugs and vaccines;
- Identify parasite factors which may be causing the rise in human infections;
- Identify novel vaccine candidates; and
- Develop a transgenic P. knowlesi model to test existing vaccine candidates for P. vivax.
The parasites produce a range of adhesive proteins enabling them to bind to specific proteins on the surface of red blood cells and establish the process of red blood cell invasion. Because of their crucial role in the invasion process, these parasite proteins are important vaccine targets. They also determine how effectively parasites can replicate and so can affect disease severity as well as determining which hosts are susceptible to malaria.
In this project, the role of these proteins during the invasion process will be investigated using the malaria parasite Plasmodium knowlesi. Highly efficient techniques will be used to genetically modify the parasite and generate parasites in which genes encoding the adhesive proteins have been deleted. This will enable the determination of which of those are essential for invasion and which can be deleted without any effect on the invasion process.
Using similar techniques fluorescent "tags" will also be added to each of the proteins coded by the target genes, so that the research team can determine where the adhesive proteins are in the cell and where they move during the invasion process. The "tags" will also allow the identification of parasite proteins that interact with the adhesive proteins as well as what they specifically bind to on the host red blood cell surface.
This will provide critical insight into the mechanism of invasion of all malaria parasites, as well as identifying precisely which parasite proteins and host proteins are required for P. knowlesi to invade human red blood cells. The latter is of particular importance as it may explain how a macaque malaria parasite is able to spread to infect humans and determine the potential for emergence of human-to-human transmission of the parasite.