The McMorran lab investigates host-pathogen interactions and how to exploit such interactions for new therapeutics, with a particular focus on malaria. Malaria is caused by the Plasmodium parasite, which is transmitted between people by mosquitoes, and infects the liver and red blood cells (erythrocytes). Clinical symptoms arise during the erythrocyte stage of infection.

We have two main research themes: Platelets and Malaria, and Developing Host-directed Therapies for Malaria. Projects in both of these areas are available for undergraduate and post-graduate students who are generally interested in

• Host-parasite interactions
• Platelet biology
• Human and mouse genetics
• Malaria drug development

Platelets and Malaria

Platelets are amongst the most abundant cells of the bloodstream, and are best known for their roles in thrombosis and haemostasis. However, platelets also have a number of important immunological functions, including in innate immunity and host defence against microbial infection. The McMorran group was the first to describe the host-defence functions of platelets in malaria and the mechanism by which they can limit parasite growth. Platelets in the circulation recognise and bind to Plasmodium-infected erythrocytes, and then release a protein called Platelet Factor 4 (PF4), which is cytotoxic and kills the parasite. Most recently we have shown the occurrence and importance of platelet-mediated protection in human malaria patients. Our current goals are to explore the biology and functions of platelets in malaria as well as other diseases affecting the bloodstream, and translate this knowledge for clinical applications. We have also capitalised on the unique anti-plasmodial properties of PF4 to generate a new drug-like peptide molecule, and aim to develop this into a novel anti-malarial treatment. Our work on these topics has been published in leading journals such as Science, Blood and Cell Chemical Biology.

Developing Host-directed Therapies for Malaria

Critical to an individual’s ability to survive malaria is their genetic makeup and ability to mount an appropriate protective response. Compared to current anti-malarial drugs, which quickly lose their effectiveness due to the pathogen developing resistance, host genes selected through evolution for their anti-malarial properties have been successful for many thousands of years. This is because the anti-malarial effects of these genes are outside the genetic control of the parasite, whereas all current drugs target parasite molecules. This research theme investigates host genetic factors that control malarial parasite growth and virulence, and how these molecules may be targeted for novel therapeutic strategies. We propose that drugs that mimic host genetic-based protection will be highly effective and resistance-proof antimalarial agents – we call this approach host-directed therapy.

Our most recent work in this area has shown how targeting one particular erythrocyte enzyme, ferrochelatase, may be used to prevent parasite growth, and the results of Phase II in human clinical trial using an anti-ferrochelatase drug. We are currently working to identify small molecule inhibitors of ferrochelatase and other parasite-required host enzymes. These can be used as tools to investigate the parasite-host molecule interactions, and in the longer-term developed into novel anti-malarial drugs. We have established biochemical assays and high-throughput screening protocols to identify new enzyme inhibitors, and medicinal chemistry projects are underway to increase the potency of some of these enzyme inhibitors.