Malaria is caused by the Plasmodium parasite, which is transmitted between people by mosquitoes, and infects the liver and red blood cells; clinical symptoms arise during the erythrocytic stage. Infections can result in flu-like symptoms and periodic fevers, which if unchecked, increase in severity and can further develop into serious life-threatening conditions, including severe anaemia, respiratory distress and coma. Millions of people living in the tropics are at risk of infection and young children, particularly those living in Africa, are most susceptible; the disease kills at least 1 million people each year. The widespread development of drug-resistant parasites is hampering ongoing control and elimination programs, motivating urgency for new ways to combat the disease. 

The main focus of my research is to understand the host response to malarial infection. Malaria survival has been a major driver in the evolutionary history of humans and many protective mechanisms have arisen that determine an individuals’ susceptibility to infection. One such mechanism involves platelets, which are able to bind parasite-infected cells and kill the parasite within. Understanding the molecular basis and clinical importance of these observations are major focuses in my group. I am also interested in discovering novel genes and pathways that protect the host during an infection, and using this knowledge to develop so-called host-directed therapies for malaria.

I am a graduate of The University of Otago, Dunedin, New Zealand and hold BSc (Hons) and PhD degrees in biochemistry. I conducted postdoctoral studies at the Institute for Molecular Bioscience, University of Queensland (1997-2006) on cystic fibrosis and host response to lung disease. Since 2006 I have lead research on the protective role of platelets in malarial infection, whilst working at the Menzies Research Institute, University of Tasmania (Senior Research Fellow; 2006-2012) and at the Australian School of Advanced Medicine, Macquarie University (Associate Professor; 2012-2014). I was appointed as an Associate Professor at the John Curtin School of Medicine (JCSMR), Australian National University (ANU) in 2014.

A hosted-directed approach to malarial treatment.

Critical to an individual’s ability to survive an infection are the genetic makeup and ability to mount an appropriate protective response. Several genetic polymorphisms are associated with increased resistance to malarial infection, and these polymorphisms are common in populations living in malaria endemic regions. Compared to the short effective half-lives of modern antimalarial drugs, genetic-based protection, which has arisen through natural selection, has provided protection for millennia. This is because the anti-malarial effects are outside the genetic control of the parasite, whereas all current drugs target parasite molecules; variant parasite strains that modify the drug or mutate its target protein can (and have) rapidly arisen through their own selective bottlenecks. 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.

Host red enzymes as targets for host-directed antimalarial therapy.

During its residence in the red blood cell, the Plasmodium parasite scavenges and co-opts many host cell molecules to sustain its own growth requirements. The aim of this project is to develop drugs that ‘starve’ parasite of these molecules, and thereby act as host-directed antimalarial therapies. Amongst these molecules are enzymes used by progenitor red cells to synthesise haem. We have discovered, using a combination of genetics, bioinformatics and molecular biology that these host enzymes are essential for the parasite. Inhibiting their functions by genetic targeting or small molecule inhibitors produces a potent anti-malarial effect. Our current work aims to evaluate which enzymes are most suited as targets for host-directed therapy, and to develop novel inhibitors as lead antimalarial compounds.

Relevant papers:

Smith CM, Jerkovic A, Puy H, Winship I, Deybach JC, Gouya L, van Dooren G, Goodman CD, Sturm A, Manceau H, McFadden GI, David P, Mercereau-Puijalon O, Burgio G, McMorran BJ, Foote SJ. Red cells from ferrochelatase-deficient erythropoietic protoporphyria patients are resistant to growth of malarial parasites. Blood. 2015;125:534-541.

Project funding:

Foote and McMorran. Griseofulvin, a novel host-directed drug. NHMRC Project Grant APP104090

Foote, McMorran and Burgio. ENU Mutagenesis and malaria chemotherapy. NHMRC Project Grant APP1047082.

The role of platelets in the protection against malarial infection

We have discovered that platelets in the circulation directly target and kill the malarial parasite as it grows inside red blood cells. This was a completely novel finding at the time as platelets are traditionally thought of as merely mediators of haemostasis and clot formation. However a large body of evidence now indicates their importance in many immunological and host defence functions, including malaria protection.  Platelets preferentially bind to Plasmodium-infected cells, become activated and release a molecule called Platelet factor 4 (PF4), which is cytotoxic to the parasite. The PF4 molecule enters the cell and parasite via red cell molecule called Duffy.  Parasites growing in red cells that lack Duffy are killed by the platelet. These discoveries implicate a relationship between the Duffy-negative allele and rates of P. falciparum infection; both are highly prevalent in African populations. Our current work aims to address a number of important questions relating to these findings, including the molecular mechanisms involved in the platelet killing function, the reasons for platelet loss early in malarial infection, and the occurrence of platelet-mediated parasite killing amongst different human populations.

Relevant papers:

McMorran BJ, Marshall VM, de Graaf C, et al. Platelets kill intraerythrocytic malarial parasites and mediate survival to infection. Science. 2009; 323:797-800.

McMorran BJ, Wieczorski L, Drysdale KE, et al. Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum. Science. 2012; 338:1348-1351.

McMorran BJ, Burgio G, Foote SJ. New Insights Into The Protective Power Of Platelets In Malaria Infection. Communicative & Integrative Biology 2013; 1;6(3):e23653.

Project funding:

McMorran, Foote and Burgio. The role of Duffy and PF4 in platelet killing of malaria parasites. NHMRC Project Grant APP1066502

How does the platelet PF4 molecule kill intraerythrocytic malarial parasites?

When platelets bind to Plasmodium-infected red blood cells, they undergo activation and release a protein called Platelet Factor 4 (PF4), which then kills the parasite. PF4 kills the parasite by specific targeting and lysis of a parasite organelle called the food vacuole. Critical also to the cytotoxic mechanism of PF4 is a red blood cell membrane molecule called Duffy antigen, which binds to PF4; PF4 (and platelets) cannot kill parasites in cells that lack the Duffy antigen. This project aims to understand the molecular pathway whereby Duffy enables uptake and targeting of PF4 into the food vacuole. Experience and/or interest in molecular biology, protein biochemistry and microscopy are essential prerequisites.

Investigating the roles for platelet-mediated killing of malarial parasites during malarial infection.

Platelets, upon binding to Plasmodium-infected red cells, kill the parasite. During a malarial infection, we know that this function of platelets is an important protective mechanism for the host. However platelet-parasitised cell interactions may also promote the so-called sequestration, or accumulation, of parasites within the capillary beds of the brain and other organs; sequestration is associated with severe and life-threatening forms of malaria infection. This project aims to investigate the platelet-parasitised red cell interaction during malarial infection, and address questions such as the fate of these cell complexes, their effects on parasite viability within affected organs, and their contribution to severe malaria pathogenesis. Experience and/or interest in murine malaria models, histopathology and malaria pathogenesis are essential prerequisites.

How are platelets activated by malaria parasite infected erythrocytes?

Platelets bind to both normal and Plasmodium infected red cells during malarial infection, however only infected red cells trigger platelet activation. This project aims to identify the host cell and parasite-expressed molecules responsible for this specific form of platelet activation, and characterise the platelet molecular signaling pathways involved.

Investigation of host haem biosynthetic enzymes required for malarial parasite growth.

During its growth in the erythrocyte, the Plasmodium parasite scavenges host molecules and enzymes for its own growth. This project aims to determine which haem biosynthetic enzymes in the host cell are utilized by the parasite, and which may suitable targets for a host-directed therapy.

Analysis of the red cell enzyme Peroxiredoxin 2 as an antimalarial target

Marianna Brizuela (Honours student)

There is proven evidence that, during the blood stage of its life cycle, Plasmodium falciparum relies heavily on human red cell enzyme peroxiredoxin 2 for hydroperoxide detoxification. It has been shown that this enzyme accounts for half the parasite´s total peroxiredoxin activity. The drug 2,3 bis (bromomethyl) quinoxaline (BBMQ) has been identified as an irreversible inhibitor of human Prx 2.  The goal of this project was to use BBMQ to evaluate the host enzyme Prx 2 as a host directed antimalarial target. 

Publications arising from the project:

Brizuela, M, Huang, H, Smith, C et al 2014, 'Treatment of erythrocytes with the 2-Cys peroxiredoxin inhibitor, conoidin A, prevents the growth of Plasmodium falciparum and enhances parasite sensitivity to chloroquine', PLOS ONE (Public Library of Science), vol. 9, no. 4, pp. e92411.

Platelet-mediated protection against malaria infection: the mechanisms involved.

Laura Wieczorski (Honours student)

The innate immune response to malaria involves the co-operation of many diverse cell types; one cell type recently identified to be important in this process is platelets. Platelets have until recently been thought to be detrimental to host, facilitating adhesion of parasitised cells to the endothelium and contributing to the development of cerebral malaria. New evidence has shown that platelets bind to infected erythrocytes and induce death of the intraerythrocytic parasite. Direct killing of intraerythrocytic parasites helps to control the early stages of malarial infection.

This study investigated the molecules involved in platelet adhesion and found that CD36, CD42b, CD61 and HABP1 were important in this process, all but CD61 were also shown to be crucial to platelet mediated parasite death. The contribution of platelet-parasite interactions to the development of thrombocytopenia was also investigated. It was found that platelet binding made a substantial contribution to platelet loss early in malarial infection.

Publications arising from the project:

McMorran, B, Wieczorski, L, Drysdale, K et al 2012, 'Platelet factor 4 and duffy antigen required for platelet killing of Plasmodium falciparum', Science, vol. 338, no. 6112, pp. 1348-1351.

An investigation of novel host-directed antimalarial therapeutics through genetic and pharmacological targeting of haem biosynthetic enzymes.

Clare Smith (PhD student).

Multiple experimental approaches were used to investigate and validate delta-aminolevulinate dehydratase (ALAD), ferrochelatase (FECH) and uroporphyrinogen-III synthase (UROS) as targets for a novel host-directed antimalarial therapy.

Publications arising from the project:

Smith, C, Jerkovic, A, Puy, H et al 2015, 'Red cells from ferrochelatase-deficient erythropoietic protoporphyria patients are resistant to growth of malarial parasites', Blood, vol. 125, no. 3, pp. 534-41.