Genome of a monkey-human malaria parasite reveals surprises
9 October 2008
P. knowlesi is particularly prevalent in South-east Asia and can cause potentially life-threatening malaria. Recent studies suggest that many P. knowlesi infections have been misdiagnosed by microscopy as P. malariae, resulting in gross underestimates of its prevalence.
The genome sequence, published today in the journal ‘Nature’, reveals a dramatic example of ‘molecular mimicry’ that is likely to be crucial for survival and propagation of the parasite in the body. Remarkably, the team found several members of a large gene family that contain sequence signatures that closely resemble a key human gene involved in regulation of the immune system. The parasite versions of the human protein are thought to interfere with recognition of infected red blood cells.
In addition to this uniquely expanded group of genes, P. knowlesi has a fundamentally different architecture of the genes involved in ‘antigenic variation’ compared to other malaria parasites. The phenomenon of ‘antigenic variation’ - where the parasite constantly changes the coat of parasitised red cells in order to avoid recognition by the host - was first discovered in P. knowlesi.
The study also emphasises the fact that, although 80 per cent of genes are shared among all sequenced malaria parasites, each species may have a unique set of tricks and disguises that help it to escape host responses and to keep itself ahead in the host-parasite interaction.
“P. knowlesi has thrown up several surprises,” says Dr Arnab Pain, project manager at the Wellcome Trust Sanger Institute. "Our study demonstrates the power of sequencing additional malaria genomes to unravel as yet undiscovered and fascinating aspects of the biology of malaria parasites.
“Unusually, the key genes that we think help the parasite to evade detection and destruction by host defences are scattered through the genome. In the other species we have examined, these genes are most often near the tips of the chromosomes."
Identified initially as a monkey parasite, P. knowlesi had been identified in only two cases of human infection before 2004. However, at that time, Professor Balbir Singh and colleagues developed DNA-based detection methods and examined samples from malaria patients in Malaysia. They showed that almost all cases of what was thought to be infection with the human parasite P. malariae were due to infection with the ‘monkey’ parasite P. knowlesi.
“Rapid and appropriate treatment is vital in cases of malaria,” says Professor Balbir Singh, Director of the Malaria Research Centre at the Faculty of Medicine and Health Sciences, University Malaysia Sarawak. “But before the development of molecular detection methods, we had been hampered by our inability to distinguish between P. knowlesi and the benign P. malariae parasites by microscopy. This parasite multiplies rapidly and can cause fatal human infections, so it is vital that doctors are aware that P. knowlesi is the fifth cause of human malaria.”
P. knowlesi is an important model for studying the way that malaria parasites interact with host cells. It is a robust species in which invasion of red blood cells can be examined in detail. The genome sequence provides an updated catalogue of proteins that might help the parasite in these first stages of infection: the team identified novel regions in the genome that help to understand the regulation of these key genes and the transport of their proteins to the red cell surface.
Image: Infected red blood cell. Anton Dluzewski, MRC NIMR and KCL, UK; Mary Galinski and Esmeralda VS Meyer, Emory Vaccine Center, Atlanta, USA; Lawrence Bannister, John Hopkins, Maryland, USA; Graham Mitchell, KCL and Guy's Hospital, UK; John Barnwell, CDC, Atlanta, USA; Tony Holder, MRC NIMR, UK.
References
Pain A. The genome of the simian and human malaria parasite Plasmodium knowlesi. Nature 2008;455:751-6.