MicrobiologyBytes

One of the main problems in fighting malaria is the speed with which the organism seems to be able to vary it’s genetic makeup. This creates two difficulties. First, antigenic variation, which makes the creation of effective vaccines very difficult, and second, the development of resistance to antimalarial drugs. Antigenic variability gives Plasmodium falciparum the ability to reinfect people who have been previously exposed to the disease. Effective immunity to malaria requires repeated infections and is slow to develop, so children under ten years of age are most susceptible to illness. The entry of malaria parasites into red blood cells during the replication cycle creates two opportunities to evade host immunity. First, infected red blood cells do not induce a CTL response due to their lack of MHC I expression. Second, malaria antigens exposed on the surface of the cell are highly variable. The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a key virulence factor which is expressed on the surface of infected erythrocytes and causes the blood cells to stick to the walls of small blood vessels, preventing infected cells from going through the general circulation and to the spleen (see: Giving malaria the slip).

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The PfEMP1 protein undergoes high clonal variation (up to 2% per generation), and Plasmodium falciparum goes through multiple generations during the course of a single human infection. The genes encoding PfEMP1 are known as the var genes. Individual P. falciparum genomes contain a diverse range of 50-150 var genes, spread across the fourteen chromosomes. Because only a limited number of the genes are expressed by each parasite, switches between different alleles of the gene during asexual reproduction leads to the production of an extremely diverse range of PfEMP1 proteins.
Each parasite devotes between 2% and 6% of its genomic DNA to its repertoire of var genes, which are clustered near the ends of the chromosomes. Changes in var expression are believed to occur by recombination-independent mechanisms. The evidence indicates that a single P. falciparum simultaneously transcribes multiple var genes during its early stages, but in the trophozoite stage, tighter transcriptional control results in the expression of a single PfEMP1 allele on the surface of an infected host cell. Clearly, understanding the basis for this genetic variation is important in being able to outwit malaria. Two recent papers in PLoS Pathogens have attempted to do just that.
In the first paper, the authors performed a full genome scan of variability in 14 different strains of P. falciparum and observed a nonrandom distribution of variation (A Systematic Map of Genetic Variation in Plasmodium falciparum. 2007 PLoS Pathogens 2, e57). Genes that are predicted to have roles in evading the host immune response or giving resistance to antimalarial drugs showed significantly higher levels of variation than other genes. Approximately 500 genes were evolving at higher than neutral rates. These genes seem to be subject to a different evolutionary clock than other genes. This observation fits well with the biology of malaria infections.
In the second paper, the authors concentrated on variation in the var genes encoding PfEMP1 (Population Genomics of the Immune Evasion (var) Genes of Plasmodium falciparum. 2007 PLoS Pathogens 3, e34). They carried out a systematic sampling of var genes from P. falciparum genomes obtained from two populations, one from Papua New Guinea and the other representing the global population of P. falciparum. Globally, there was no limit to the number of var genes seen because strains rarely shared var genes. In contrast, in the Papua New Guinea samples, var gene numbers were restricted due to high levels of gene sharing, and most of the var genes seen were only found in that population. It became apparent that recombination is important to the evolution of var genes in Papua New Guinea. The fact that there are distinct var genes in different populations may have consequences for the spread of malarial disease from one geographic area to another.

With effective malaria vaccines still years away, this type of population genetics approach will be important in exploring the geographic diversity of var genes across the globe and may help to determine vaccine formulations and strategies.

This entry was posted on Monday, April 16th, 2007 at 9:30 am and is filed under Biology, Genetics, Health, Malaria, Medicine, Microbiology, Parasitology, Podcast, Science. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed.