Malaria research in the post-genomic era

Abstract

For many pathogens the availability of genome sequence, permitting genome-dependent methods of research, can partially substitute for powerful forward genetic methods (genome-independent) that have advanced model organism research for decades. In 2002 the genome sequence of Plasmodium falciparum, the parasite causing the most severe type of human malaria, was completed, eliminating many of the barriers to performing state-of-the-art molecular biological research on malaria parasites. Although new, licensed therapies may not yet have resulted from genome-dependent experiments, they have produced a wealth of new observations about the basic biology of malaria parasites, and it is likely that these will eventually lead to new therapeutic approaches. This review will focus on the basic research discoveries that have depended, in part, on the availability of the Plasmodium genome sequences.

Figure 1

Diagram of the malaria parasite’s lifecycle. Malaria is transmitted by the bite of a mosquito in which hundreds of sporozoites are released into the vertebrate host’s bloodstream. The parasites eventually migrate to the liver, transversing some cell types such as Kupfer cells but forming a parasitophorous vacuoles in hepatocyte. At this stage they can either remain dormant as a hypnozoite form (P. vivax or P. ovale), or initiate development that results in the production of thousands of merozoites. The parasites then induce detachment of the infected hepatocyte, allowing it to migrate to the liver sinusoid where budding of parasite filled vesicles called merosomes occurs. The new merozoites quickly invade erythrocytes where they replicate, sometime synchronously, in a cycle that may correspond to the cycle of fever and chills in malaria. In response to a cue that is not well understood some parasites differentiate into male and female gametocytes, which are forms taken up by the mosquito, and can live quiescently in the bloodstream for weeks. Once they enter the mosquito in the bloodmeal they rapidly transition into activated male and female gametes. The motile and short-lived diploid parasite form, the ookinete, migrates out of the bloodmeal, across the peritrophic matrix to the midgut wall where an oocyst is formed. After a meiotic reduction in chromosome number thousands of sporozoites are formed within the oocyst. Eventually the oocyst ruptures and the sporozoites migrate to the salivary gland where they await transfer to the vertebrate host.

Figure 2

Export pathways shared by eukaryotic pathogens. A. In erythrocytic stages of the parasite exports proteins containing a Pexel/VTS motif across the parasitophorous vacuole into cytoplasm of the infected erythrocyte ,. Some of these proteins eventually reach the surface of the infected erythrocyte where they have a role in antigenic variation and immune evasion. B. In plant pathogens a similar pathway is used with the effector proteins often interfering with plant innate immune defences . C. In the liver stages of a malaria infection, CSP, and potentially other proteins, are released into the hepatocyte cytoplasm. One model is that these proteins may interfere with import of nuclear factor KB , a protein needed for activation of human innate immune responses.