Malaria remains one of the most devastating infectious diseases of humans and is caused by large-scale infection of the blood with unicellular Plasmodium parasites.
Plasmodium falciparum is the most pathogenic species to infect humans and caused more than 400,000 deaths in 2015. The ability to avoid the immune system accounts for much of the success of this highly virulent parasite and this is in part due to its ability to export adhesive Velcro-like PfEMP1 proteins onto the surface of the red blood cells (RBCs) that they infect, which enable the RBCs to sequester in the peripheral blood, thereby preventing their clearance through the spleen.
Plasmodium parasites also export many other proteins into their host cells that are crucial to parasite survival accounting for a substantial 5-8 percent of its predicted proteome. Recently we achieved a breakthrough in understanding the export of malaria proteins with the discovery of the export machine that provides a selective gateway for parasite proteins to gain access to the RBC cytoplasm. Termed PTEX, this machine contains 5 core proteins whose atomic structures we are attempting to solve so we can understand how the complex is constructed and how it works as an export machine. PTEX has the credentials to make an excellent drug target since blocking it would halt the functions of hundreds of other parasite proteins by preventing them from reaching the final destinations with the RBC where they operate.
At the molecular level we will attempt to understand how PTEX recognises its protein cargo and how it then translocates the cargo across a membrane into the RBC. We are also investigating if cycles of assembly and disassembly are part of how the PTEX complex normally functions with the help of accessory proteins. This information will be used to aid the design of drug inhibitors that could become future antimalarial treatments.
The malaria parasite is transmitted from human to human by the Anopheles mosquito and after a brief period inside the human liver, the parasite begins infecting red blood cells where they can multiply to extraordinarily high numbers. It is at this point that the fever-like symptoms of the malarial disease occur. This is sometimes followed by life threatening complications such as coma and severe anaemia.
Antimalarial drugs are the main weapons used to combat infection but parasites are starting to become alarmingly resistant to the latest frontline drugs. For this reason new drug targets need to be identified and new medicines developed for future use. Thankfully, thousands of potent parasite killing compounds have been discovered but their targets in the parasite are unknown.
One potential suite of targets are the protein trafficking pathways used by parasites to shuttle proteins around not only their own cells but also those of the human red blood host cells (RBC) they infect. These so-called exported proteins, modify the RBCs so the parasite can evade host immunity and rapidly reproduce.
We have discovered several drugs that not only block parasite protein trafficking but also prevent the parasite from taking up nutrients via the RBC. These drugs cause parasite death and the aim of this project is to help evaluate the biological targets of these drugs and how to make the drugs more potent and specific for potential clinical applications.
Highlights of our work include three high profile publications in the leading scientific journal Nature, in 2009, 2010 and 2014 that collectively have been cited nearly 600 times by other researchers.
publications in the leading scientific journal Nature that collectively have been cited nearly 600 times by other researchers.
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