Understanding how malaria parasites remodel the red blood cell of humans
Project type
Honours and/or PhD
| Supervisor(s) | Division | |
| (Primary) | Infection and Immunity | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Infection and Immunity | .(JavaScript must be enabled to view this email address) |
Details of project
The Plasmodium falciparum erythrocyte binding protein 1 (PfEMP1) is expressed by the asexual blood stage of P. falciparum and trafficked across three membranes before being inserted into the infected host cell membrane. It is the major virulence protein of P. falciparum and responsible for antigenic variation, cytoadherence and modulation of host responses.
Our aim is to understand how PfEMP1 is trafficked to the P. falciparum-infected erythrocyte membrane. This project will determine the function of key regulators that we have identified previously, in trafficking of PfEMP1 to the erythrocyte surface. This will involve the construction of genetically modified malaria parasites that lack the function of these genes or express altered versions to enable us to determine the effect on PfEMP1 trafficking. It will also involve immuno-precipitation experiments to identify other proteins with which they interact. We will use antibodies specific to the proteins and, to definitively identify which proteins are in a complex, we will employ a combination of two dimensional gel electrophoresis and mass spectrometry analyses.
This project will analyse the subcellular localisation of these proteins by both light and electron microscopy to help understand their function. It may also involve microscopy of live parasites that express fluorescently tagged proteins to study the movement of these proteins and structures in the parasite-infected red blood cell. Our hypothesis is that specific proteins are required for different steps in trafficking of PfEMP1 to the P. falciparum-infected erythrocyte membrane and this project will aim to unravel the role of some of these in this important process critical for virulence of the malaria parasite.
This project will be suited to both Honours and PhD candidates.
Project references
- Marti M, Good RT, Rug M, Knuepfer E, and Cowman AF. Targeting malaria virulence and remodelling proteins to the host erythrocyte. Science. 2004;306:1930-1933.
- Goldberg DE, Cowman AF. Moving in and renovating: export of proteins into the Plasmodium-infected erythrocyte. Nat. Rev. Micro. 2010;8: 617-621.
- Maier AG, Rug M, O'Neill MT, Brown M, Chakravorty S, Szestak T, Chesson J, Wu Y, Hughes K, Coppel RL, Newbold C, Beeson JG, Craig A, Crabb BS, Cowman AF. Exported proteins required for virulence and rigidity of Plasmodium falciparum-infected human erythrocytes. Cell. 2008;134: 48-61.
Research interests
Malaria parasites undertake a large-scale infection of the bloodstream where they survive inside erythrocytes by drastically renovating them. This provides the parasites with a home to hide from immune defences and to obtain the nutrients they require for growth and replication.
In order to accomplish this cellular renovation, the intracellular parasite exports hundreds of proteins into the erythrocyte to commandeer it for its own purposes. Exported proteins of the malaria parasite, Plasmodium falciparum, interact with proteins of the erythrocyte membrane and induce substantial changes in the morphology, physiology and function of the host cell. These changes underlie the pathology that is responsible for the deaths of 1-2 million children every year due to malaria infections.
The advent of molecular transfection technology, including the ability to generate deletion mutants and to introduce fluorescent reporter proteins that track the locations and dynamics of parasite proteins, has increased our understanding of the processes and machinery for export of proteins in P. falciparum-infected erythrocytes and provided insights into the functions of the parasite protein exportome. We are interested in understanding the molecular basis of how the parasite achieves its home renovation.
Research theme
Infectious diseases
Scientific discipline
- Biochemistry
- Cell Biology
- Microbiology
- Molecular Biology
- Proteomics
Keywords
malaria, human red blood cells, Plasmodium, disease