Unravelling red cell rosetting 1/10/02. By Caroline Cross Alex Rowe is investigating why some forms of the malaria parasite cause red blood cells to clump together and form harmful 'rosettes'.

Malaria-infected red blood cells sometimes bind to uninfected red blood cells to form clumps, called rosettes. The rosettes can obstruct flow in small blood vessels and lead to tissue damage and severe malaria disease.

"The main aim of my research is to understand how rosettes form and work out whether it would be possible to come up with drugs or vaccines that could inhibit rosette formation and prevent some cases of severe malaria," says Dr Alex Rowe, a Wellcome Trust Senior Research Fellow in Basic Sciences, at the University of Edinburgh.

"Although only a minority of Plasmodium falciparum strains cause rosettes to form, there is good evidence that rosettes contribute to malaria disease," she says. "In fact, in studies of African children, it is the only property of the parasite that is clearly linked to severe malaria."

Dr Rowe has already pinpointed the cause of the clumping – a family of parasite proteins known as PfEMP-1 (P. falciparum erythrocyte membrane protein-1). The proteins come in a range of guises, the various forms being encoded by a family of genes called var genes, which are dispersed throughout the malaria parasite's genome.

Any one of about 50 versions of the PfEMP-1 protein can be produced by the parasite while it is growing inside the red blood cell (during its 48-hour asexual life cycle). The PfEMP1 protein is then inserted into the membrane of the infected red blood cell. Some members of the PfEMP-1 family are particularly sticky and bind to receptors on other red blood cells; the infected and uninfected cells then clump together to form rosettes. Other PfEMP-1 variants prefer to bind to the inner edges of blood vessels in major organs, a phenomenon known as sequestration, which is also important in severe malaria.

The malaria parasite uses its closet of PfEMP-1 proteins to disguise itself from the host's immune system – as antibodies are raised against a particular PfEMP-1 form, so the parasite changes to express a different PfEMP-1 variant.

But sometimes it prefers to wear a familiar guise. Dr Rowe and colleagues were surprised to find that a few PfEMP-1 variants are expressed by many different parasite strains from around the world.

"We don't yet understand the function of these well-conserved genes. They are not involved in rosetting but may be important in other host–parasite interactions. It may be that these well-conserved genes are very important for the parasite to survive; it might be for transmission or something else we haven't considered," she suggests. Understanding the diversity of PfEMP-1 variants, and what makes particular variants of PfEMP-1 cause rosetting, are major foci of Dr Rowe's current research.

The team is also investigating how PfEMP-1 sticks to uninfected red blood cells. Dr Rowe has found that PfEMP-1 binds to a host protein called complement receptor-1 (CR1) on the surface of uninfected red blood cells. "CR1 is particularly interesting because there are a number of genetic variations in the human CR1 gene that are found at very high frequencies in individuals in malaria-endemic countries but not in countries where there is no malaria," she says. Dr Rowe and colleagues from the USA, Mali and Papua New Guinea are currently investigating the possibility that these variations might affect rosetting and therefore susceptibility to severe malaria.

Antibodies that prevent rosette formation are often made by adults and adolescents who have developed immunity to severe malaria. Dr Rowe hopes to find features common to all the PfEMP-1 variants that cause rosettes to form; these regions of the protein could then be used as targets for vaccines that could lead to a similar immunity. "People would still get infected with the malaria parasite, but rosetting, and therefore severe disease, could be prevented," she says. "Although not all severe malaria is due to rosetting, it is probably an important factor in some cases. If we can block rosette formation we may be able to reduce the number of deaths from the disease."

Dr Alex Rowe is at the Institute of Immunology and Infection Research, University of Edinburgh.

Links

Alex Rowe, University of Edinburgh: research page

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