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London School of Hygiene & Tropical Medicine Malaria Centre

Blog | New insights into malaria parasite escape from red blood cells

 
Malaria parasite among red blood cells.
 

Malaria parasite among red blood cells.

20 February 2018
By Mike Blackman

An improved understanding of how the malaria parasite multiplies in the bloodstream of infected patients may help the development of new types of antimalarial drugs, according to new research published in Nature Microbiology.


The symptoms of malaria are caused by replication of the parasite in red blood cells. When it invades a red cell, the parasite surrounds itself by an internal compartment, or vacuole, within which it divides. To eventually escape from the red cell and infect new cells, the newly-formed parasites have to break down both the internal vacuole and the red cell membrane.

A team of researchers from The London School of Hygiene & Tropical Medicine, Francis Crick Institute, Birkbeck College and Kings College London have now shown that two parasite proteins called SUB1 and SERA6 are essential for the parasite to escape from red blood cells.

Mike Blackman, Professor of Molecular Parasitology at the London School of Hygiene & Tropical Medicine, and Group Leader at the Francis Crick Institute said: “We have been studying SUB1 for some time but we didn’t know its precise role. Our new work has shown that SUB1 is needed to break the internal vacuole that the parasite divides in. What’s more, we’ve found that SUB1 then immediately activates SERA6, which breaks down the red blood cell membrane.”

By comparing parasites lacking SERA6 with normal parasites, the team went on to examine how SERA6 ruptures the red cell. They found that SERA6 works by attacking a part of the red cell called the cytoskeleton. Michele Tan, joint-first author of the paper explains: “The cytoskeleton resembles a chicken wire-like mesh that is attached to the underneath of the red cell membrane and is crucial for its strength. SERA6 snips the mesh in a very precise manner, fragmenting it and ripping open the  red cell membrane.”

Both SUB1 and SERA6 belongs to a family of enzymes called proteases, which are already known to be good drug targets in other diseases. Dr James Thomas, joint first-author of the paper said: “Resistance of the malaria parasite to commonly used antimalarial drugs is growing around the world, so there is a need for new antimalarials that work in different ways to existing therapies. We are already working with GSK to see if we can design new drugs that work by blocking the activity of SUB1. We would now like to do the same for SERA6”

The team now want to understand how SUB1 breaks the vacuole and how SERA6 is activated by SUB1. The Blackman group are also collaborating with David Baker’s group at the London School of Hygiene & Tropical Medicine to investigate the signals that control parasite release and red cell invasion.  Together they have previously shown that SUB1 is activated by a third enzyme called PKG which is a focus of the Baker lab. As Mike Blackman says: “The Baker lab have already developed excellent PKG inhibitors in partnership with LifeArc. Our new information shows us that we might be able to develop drug combinations that target all three of these enzymes at once, in a kind of triple-whammy. This would make it much more difficult for the parasites to become resistant to the drugs.”

 

Publication

 

James A Thomas, Michele SY Tan, et al. A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells. Nature Microbiology. DOI: 10.1038/s41564-018-0111-0.