Malaria genomes under the knife

The genomes of two species of malaria parasites have been sequenced in an international collaboration that sheds new light the basic biology of the parasites and potential pathways through which they evade their hosts’ immune systems.

Plasmodium vivax and Plasmodium knowlesi join the deadly Plasmodium falciparum in having their genomes sequenced. P. vivax is the major cause of malaria in Asia and the Americas, and has generally been considered benign as it is rarely fatal.

It is becoming resistant to common drugs, however, and its pathology is becoming more severe. It is also a difficult parasite to study as it cannot be cultured continuously in the laboratory.

P. vivax is responsible for between 25 and 40 per cent of the approximately 515 million cases of malaria each year. As a team of international researchers describe in a paper published in Nature yesterday, although it is seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after the primary infection has cleared.

The team, led by Dr Jane Carlton from the New York University Medical Centre and including Professor Brendan Crabb, Dr Paul Gilson and Dr Toby Sargeant of Melbourne’s Walter and Eliza Hall Institute of Medical Research, found that P. vivax resembles other malaria parasites in gene content and metabolic potential, but has several novel gene families and potential invasion pathways not previously recognised.

Of particular interest are the merozoite surface protein (MSP) families, especially MSP3 and MSP7, which may have developed as a means to enhance immune evasion.

As Elizabeth Ann Winzeler of the Scripps Institute in California writes in a review article in the same issue, an exciting recent development in Plasmodium research has been the identification of a protein export motif, called PEXEL. Many of the proteins that contain this motif seem to be involved in creating the knobby structures seen in P. falciparum-infected red blood cells that make the parasite stick.

Interestingly, this motif is found in P. vivax despite its proteins not adhering to the infected cell.

The other genome to be sequenced, P. knowlesi, was thought to infect only the kra monkey but is now known to be a significant cause of human malaria.

In a study led by Arnab Pain from the Wellcome Trust Sanger Institute in Cambridge in the UK, the researchers found that while this parasite has a close phylogenic relationship to P. vivax, there are major differences, including host blood cell preference and an absence of the dormant liver stage of P. vivax.

The team, which also includes WEHI’s Professor Alan Cowman and Toby Sargeant, found major differences in both content and organisation of the P. knowlesi genome from P. falciparum and P. vivax at the host-parasite interface, suggesting that the different malaria species have evolved different mechanisms for survival within their hosts.

They also found that one family of genes in P. knowlesi shares common sequences with a host protein, which could represent a form of mimicry whereby the parasite impersonates the host to evade detection by the immune system.

“Comparative genomics of the neglected human malaria parasite Plasmodium vivax” by Carlton et al [doi:10.1038/nature073227]; “The genome of the simian and human malaria parasite Plasmodium knowlesi” by Pain et al [doi:10.1038/nature070306] and “Malaria research in the post-genomic era” by Wheeler [doi:10.1038/nature07361] are published in Nature.