Discovering how malaria parasites survive inside human red blood cells

Malaria remains a major global health burden causing hundreds of millions of debilitating infections per year that tragically result in over half a million deaths. 

The mosquito borne Plasmodium parasites, which cause malaria, invade and grow inside human red blood cells (RBCs). RBCs are ideal places for parasites to live because they are relatively invisible to the immune system, and they can be taken up by mosquitoes for transmission to others. 

The disadvantages are that RBCs are nutrient poor and are monitored by the spleen where circulating parasite infected RBCs are destroyed. For these reasons, malaria parasites extensively modify their RBCs to obtain supplementary nutrients, elude the immune system and avoid destruction in the spleen. 

Within an infected RBC, the parasite hides within a specialised membrane sac termed the parasitophorous vacuole. To survive within this protected niche, the parasite must export hundreds of proteins into the RBC compartment. These proteins help the parasite take up nutrients from its host and are also involved in remodelling the RBC to make it sticky; by sticking to the walls of blood vessels, the infected RBC avoids clearance by the spleen and the parasite has the opportunity to grow, cause disease symptoms, and transmit to others.  The proteins involved in RBC remodelling enter the RBC following passage through a protein translocon called PTEX.  

Exported proteins contain a molecular barcode, called a PEXEL motif, that is scanned by PTEX, allowing only a specific subset of parasite proteins access to the RBC. Of these exported proteins, ~70 are believed to be essential for parasite survival. Importantly, the roles of many of these essential proteins remain completely undefined, meaning that we have no idea how they contribute to parasite survival. If we can decipher how these proteins work, we are likely to uncover completely new ways in which the parasite can be targeted and killed by new therapeutics. Discovering how these essential exported proteins contribute to parasite survival is the key focus of this project. 

This project involves an array of state-of-the-art molecular biology, biochemical and microscopy techniques to define the function of essential exported proteins in malaria parasites. This work will be completed in the two main species of malaria that can be cultured in the lab: P. falciparum and P. knowlesi.