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

Malaria caused by Plasmodium falciparum parasites remains a major global health problem with about 40% of the world’s population at risk of infection.

Although there have been major reductions in disease impact over the last 10 years due to increased malaria control, this downward trajectory has recently stalled.

Of particular concern is the global spread of parasites resistant to frontline artemisinin combination therapies. This emphasizes a critical need to discover new drugs with novel targets to fight malaria.

Malaria is caused by large scale parasite infection of the body’s red blood cells (RBCs). We are particularly interested in how parasites invade RBCs because if this could be stopped then the parasite infection could be arrested. There are probably hundreds of proteins involved in invasion and the most obvious players have been studied.

To identify novel invasion proteins and to understand their roles we propose to screen drug libraries against parasites to find those that kill parasites and determine how potent they are.

We will then determine if these growth inhibitory drugs act by blocking parasite invasion of human RBCs.

The drug will be used as tools to better understand invasion using two main approaches:

1. Live cell video microscopy will be used to observe drug -treated parasites as they try to invade RBCs so we can determine which invasion step is being blocked.
2. Select for parasite resistance to the compounds and then identify the mutations responsible in the target gene of the tool compound. If the tool compounds have a unique and interesting mechanisms of action they could be developed into future antimalarial drugs.

Skills acquired during this project will be in cell culture, advanced microscopy and AI analysis, genomics and molecular biology.