The McMorran group works in the Division of Immunology and Infectious Disease at ANU’s prestigious John Curtin School of Medical Research. We investigate the two major cells of the blood, red blood cells (RBC) and platelets, and the important roles of these cells play in various human diseases affecting the circulation. We have a strong track record in discovery science, having identified platelets as innate immune protective cells in malarial infection and that platelets are regulators of erythrocyte turnover. Our current work explores the biology and biochemistry that underpins these remarkable platelet functions. We are interested in both the broader physiological significance of platelet-RBC interactions in the bloodstream, how these cells impact on host susceptibility and resistance to malaria, and how they contribute to the pathogenesis of chronic conditions affecting platelet and erythrocytes, as well as translating this knowledge for clinical applications. 

In other collaborative work, we also host projects investigating the genetic causes of chronic kidney disease in an Indigenous Australian community. The projects listed below are available for undergraduate and post-graduate students interested in immunology and parasitology, malaria drug development, haematology and platelet function, or human genetics.

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. I currently serve roles in undergraduate teaching (course convener) and am the Associate Director of Higher Degree Research at the John Curtin.

The role of platelets in the protection against malarial infection. 

Platelets best known for their roles in haemostasis and thrombosis in the bloodstream. They also have many functions in the immune system, including in innate immunity and host defence against microbial infection. The McMorran group was the first to describe that platelets play a protective role in malarial infection (McMorran et al. 2009). Platelets bind to Plasmodium-infected erythrocytes, become activated and release a molecule called Platelet factor 4 (PF4). The PF4 can enter and accumulate inside the parasite, and then kill the parasite by inducing lysis of the digestive vacuole (DV), which the parasite needs to survive and reproduce itself. The PF4 molecule enters the cell and parasite via red cell membrane protein called Duffy, and parasites growing in red cells that lack Duffy are not killed by the platelet (McMorran et al. 2012). Our discoveries implicate a relationship between the Duffy-negative allele and rates of P. falciparum infection; both are highly prevalent in African populations. Although our studies (in non-African groups) have also shown the occurrence and importance of platelet-mediated protection in malaria patients (Kho et al. 2018). Current projects are aimed at understanding the molecular mechanisms involved in the platelet killing function and the reasons for platelet loss early in malarial infection (Figure 1).

Developing host-inspired molecules for treating malaria. 

We have taken inspiration from 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 lead molecule, called PDIP (platelet factor 4 dimer internalisation peptide) possesses specific and potent activity distinct from other antimalarial drugs, whereby it translocates and accumulates inside Plasmodium-infected cells and kills the parasite by inducing lysis of the digestive vacuole (DV), an organelle that degrades and recycles the host cell contents. This killing activity is attributed to a paired amphipathic alpha helical domain of PF4 which enables it to interact and cross cell membranes; PDIP is a cyclised alpha-hairpin peptide that replicates this domain (Lawrence et al. 2018; Palombi et al. 2023).

 Our current goals are to investigate PDIP structure-function relationships to understand the parasite killing mechanism and optimise its potency. Working with collaborators, we are producing peptide-drug conjugates (Palombi et al. 2023), where PDIP is fused to antimalarial drugs, to re-functionalise and enhance the activity of the peptide and improve drug effectiveness.

The function of platelets in regulating RBC turnover. 

Aged or senescent RBC form in our bloodstream approximately 120 days after they are produced in the bone marrow. Removal of these cells is critical for maintaining a constant number of RBC in the blood and avoiding potential problems they can cause like thrombosis. We have discovered a previously unrecognised physiological function for platelets in the removal of old or senescent RBC, whereby platelets recognise and bind senescent RBC in the circulation and produce platelet-red blood cell complexes (Ningtyas et al 2024 in press). These complexes target the destruction of old cells in the spleen via phagocytosis. We think platelets are therefore important for binding and clearing senescent RBC, and disruptions in platelet count or complex formation and clearance negatively affect RBC homeostasis. When this mechanism is disturbed by diseases such as thrombocytopenia and asplenia, older red cells and complexes remain in the circulation. This may explain why people with these conditions experience and elevated risk of thrombosis.

There are several new lines of enquiry and projects stemming from these findings:

What are the molecules on platelets and senescent red blood cells that drive complex formation?

How do platelets stimulate phagocytosis of red blood cells?

How do anti-thrombotic drugs affect P-RBC complex formation and clearance?

Like the fate of platelet-bound senescent red blood cells, does platelet binding to Plasmodium-infected cells drive their clearance from the bloodstream?

Genes causing chronic kidney disease in Indigenous Australians.

Kidney disease seriously affects the Australian Indigenous population with it killing more people from remote communities than anything else. We have studied the genetics of this disease and have identified several genes and genetic variants that contribute to the disease. These genes are involved in kidney development and inflammation. We are making mice and cell lines with these genetic variants in order to investigate how these may cause kidney disease and test the efficacy of potential therapeutic interventions.

Related reading

McMorran, B.J., et al., Platelets kill intraerythrocytic malarial parasites and mediate survival to infection. Science, 2009. 323(5915): p. 797-800.

McMorran, B.J., et al., Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum. Science, 2012. 338(6112): p. 1348-51.

Kho, S., et al., Platelets kill circulating parasites of all major Plasmodium species in human malaria. Blood, 2018. 132(12): p. 1332-1344.

 Lawrence, N., A. S. M. Dennis, A. M. Lehane, A. Ehmann, P. J. Harvey, A. H. Benfield, O. Cheneval, S. T. Henriques, D. J. Craik, and B. J. McMorran. 2018. 'Defense Peptides Engineered from Human Platelet Factor 4 Kill Plasmodium by Selective Membrane Disruption', Cell Chem Biol, 25: 1140-50.e5.

Palombi, I. R., N. Lawrence, A. M. White, C. L. Gare, D. J. Craik, B. J. McMorran, and L. R. Malins. 2023. 'Development of Antiplasmodial Peptide-Drug Conjugates Using a Human Protein-Derived Cell-Penetrating Peptide with Selectivity for Infected Cells', Bioconjug Chem, 34: 1105-13.

Ningtyas, D.C., et al., Platelets mediate the clearance of senescent red blood cells by forming pro-phagocytic platelet-cell complexes. Blood, 2024. In press. https://doi.org/10.1182/blood.2023021611

Thomson, R.J., et al., New Genetic Loci Associated With Chronic Kidney Disease in an Indigenous Australian Population. Front Genet, 2019. 10: p. 330.

Students interested in studying host-pathogen interactions, anti-plasmodial drug development, haematology and platelet and erythrocyte biology, or human genomics and kidney disease can contact A/Prof Brendan McMorran for more information about available projects.

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.