Melbourne researchers discover malaria resistance mutation

A new pathway for the invasion of red blood cells by the malaria parasite Plasmodium falciparum has been discovered by Melbourne researchers based at the Walter and Eliza Hall Institute (WEHI).

The scientists, led by Prof Alan Cowman and Dr Alex Maier, found the pathway by examining a mutation found in a Melanesian population in Papua New Guinea that appeared to lead to increased resistance to infection by malaria.

The population carried a mutation in the gene for glycophorin C (GYPC), deleting one of the exons. This mutation, also called the Gerbich mutation, had been known for some time, and was thought to possibly have a role in malaria resistance, said Cowman.

But the interaction between GYPC and the malarial protein Erythrocyte-Binding Antigen 140 (EBA140) was unknown, until Cowman and his team showed that the receptor on red blood cells, or erythrocytes, for EBA140 was the GYPC protein.

The Gerbich mutation, while having no apparent deleterious effect on the carrier, blocked the malarial protein erythrocyte-binding-antigen 140 (EBA140) from binding to GYPC.

Significantly, this also caused a reduction in the level of infection by the parasite, as it appears that the number of pathways that are used by P. falciparum to enter the red blood cells correlates with the level of infection and severity of the disease. The natural selection of the beneficial mutation has resulted in a high frequency of the gene in the Melanesian populations of coastal Papua New Guinea where malaria is endemic.

The discovery is also important, according to Cowman, because of the need to understand exactly how the malaria parasite infects cells in order to design effective vaccine candidates and appropriate drug targets.

"Our aim is to understand how malaria infects blood cells," he explained.

He noted that while EBA175, which binds to glycophorin A (GYPA) and facilitates invasion through that receptor, was an important vaccine candidate, other invasion pathways such as the EBA140/GYPC system would also be necessary for effective vaccination.

The new invasion pathway is the fourth known pathway used by the parasite, and Cowman believes there could be another three or four more yet to be discovered.

It's a good example of co-evolution, he said, as the parasite evolves alternative pathways to get around protective mutations in the human receptors. EBA140 is very similar to the main EBA175 protein and similarly, GYPC is related to GYPA.

"We think it's important to understand the function [of these pathways] so that we can rationally select vaccine candidates and drug targets. With the malaria genome sequenced, there are a lot of vaccine candidates and drug targets... we believe that knowing what they do first is important," Cowman said.

Ultimately, Cowman and his team hope to start looking at vaccines and drug targets, but not before more research into the discovery.

The research is published in the January 2003 issue of Nature Medicine.

Reference: Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations. AG Maier, MT Duraisingh, JC Reeder, SS Patel, JW Kazura, PA Zimmerman, AF Cowman. Published online: 9 December 2002, doi:10.1038/nm807