Discovering the targets of drugs that stop malaria parasites invading red blood cells

Malaria is still one of the world’s most important infectious diseases. Despite a halving in the impact of malaria over the last 10 years, the emergence of multi-drug resistant parasites is a major threat to further advances.

There is an urgent and ongoing need for the development of new antimalarial drugs, especially compounds that have completely novel mechanisms of action from those currently in use, and compounds that simultaneously target the two major causative agents of malaria: Plasmodium falciparum and Plasmodium vivax. 

One highly potent novel target is the pan-Plasmodium protein export trafficking complex known as PTEX, originally identified by our team.

Malaria parasites proliferate inside the body’s red blood cells (RBCs) and around the parasite surface are large funnel-like PTEX machines that unfold and push parasite proteins into the RBC compartment where these proteins perform important functions. We have recently discovered that parts of the PTEX machine are also located inside the parasite where they bind to exported proteins.

We now hypothesise that certain PTEX components may first recognise exported proteins inside the parasite and then escort these proteins to the parasite surface where the whole PTEX funnel reassembles to export proteins into the RBC. After this, PTEX may disassemble to repeat the process.

To support our assembly hypothesis, this Honours project will involve engineering parasites that express exported reporter proteins that can tag any nearby proteins including PTEX and its supporting systems. We will then capture the tagged proteins and identify them to help fully understand how PTEX assembles and dissembles in different compartments of the parasite infected RBC.

Laboratory techniques will include parasite culture, protein purification, mass spectrometry and parasite molecular biology.