Discovering how the malaria parasite creates a protective niche in human red blood cells

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

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

The disadvantages are that RBCs are small, nutrient poor and their quality is monitored by the spleen where parasite infected RBCs are destroyed. For these reasons parasites extensively modify their RBCs to obtain supplementary nutrients and to avoid passage through the spleen.

Parasites modify their RBCs by exporting hundreds of proteins into the RBC compartment which surrounds the parasite. Exported proteins gain entry to the RBC compartment by passage through a protein translocon channel called PTEX. Exported proteins contain a molecular barcode called a PEXEL motif that is scanned within the parasite and by PTEX outside the parasite.

There are many steps during the export journey which are poorly understood, and this project seeks to address this by using different PEXEL proteins which either remain trapped inside or just outside the parasite or are fully exported into the RBC compartment.

The PEXEL reporters will contain a TurboID biotinylation enzyme which will tag nearby proteins allowing us to determine the factors that assist the PEXEL reports to be exported out of the parasite and into the RBC.

This project could help inform the development of new drugs that prevent parasites from successfully infecting human RBCs.

Skills that will be acquired during this project include parasite cell culture, immunofluorescence microscopy, protein export assays and mass spectrometry.