Scientists in Australia have made a breakthrough discovery about how the malaria parasite makes red blood cells too sticky and rigid for the the immune system to deal with that could one day lead to effective treatment against a devastating disease that infects and debilitates 600 million people and kills nearly 3 million every year, with children and pregnant women being the most affected.
The study that led to the discovery is published in the 11th July issue of the journal Cell and is the work of Professor Alan Cowman, at the Walter and Eliza Hall Institute (WEHI) of Medical Research in Melbourne, Australia and other colleagues from WEHI and other research centres throughout the world.
Plasmodium falciparum accounts for 80 per cent of human malarial infections and has the highest rates of complications and deaths. It is spread by Anopheles mosquitoes and is more prevalent in sub-Saharan Africa than anywhere else in the world.
The parasite is injected into the human bloodstream via bites from an infected mosquito. Once in the bloodstream it sets about hijacking red blood cells and turning them into “sticky sacks” housing up to 32 new daughter parasites. The sticky cells adhere to blood vessel walls, which stops them being transported to the spleen where the immune system would be able to destroy them.
Using a large scale gene knockout strategy, Cowman and colleagues found 8 genes that encode proteins that help to transport the parasite’s adhesion factor PfEMP1 to the surface of infected red blood cells, where “sticky knobs” act like platforms that anchor the PfEMP1.
One of the exciting features of the discovery is that Cowman and colleagues found that by removing one of the proteins they could almost completely disrupt the parasite’s ability to make the hijacked red cell stick to blood vessel walls.
They concluded that the 8 proteins collectively function as a pathogen secretion system, similar to bacteria. These are potential targets for developing treatments against malaria. In a press statement, the researchers said that:
“This discovery has greatly enhanced our understanding of how the parasite commandeers the red blood cell for its own survival and avoids our immune defences. It also suggests that a drug that inactivates an essential adhesion protein would be an effective anti-malarial.”
The problem with current anti malaria drugs is that they aim to disrupt the metabolism or biology of the parasite directly. But unfortunately the parasite adapts and becomes resistant to such attacks, so a completely different strategy such as this discovery, which would eventually mean that the parasite would not be able to stop the hijacked red cells from entering the spleen and be destroyed by the immune system is likely to be more effective, suggested the researchers.
“Exported Proteins Required for Virulence and Rigidity of Plasmodium falciparum-Infected Human Erythrocytes.”
Alexander G. Maier, Melanie Rug, Matthew T. O’Neill, Monica Brown, Srabasti Chakravorty, Tadge Szestak, Joanne Chesson, Yang Wu, Katie Hughes, Ross L. Coppel, Chris Newbold, James G. Beeson, Alister Craig, Brendan S. Crabb, and Alan F. Cowman.
Cell, Vol 134, 48-61, 11 July 2008
Sources: WEHI press statement, journal abstract.
Written by: Catharine Paddock, PhD