(Plasmodium falciparum)
Plasmodium falciparum is a causative agent of human malaria, a persistent, recurrent and highly variable disease. The success of the parasite in evading host immunity is attributed to the process of antigenic variation occurring in the population as a whole as well as the individual organism.

Population diversity

The ability of Plasmodium falciparum to reinfect previously exposed individuals is due to the existence of phenotypically variant strains of the parasite in endemic areas. The epidemiology of malaria is heavily dependent upon this variance. Clinical studies have shown that
immunity to malaria requires repeated infections and is slow to develop, and that children under ten years of age are the most susceptible to grave illness and fatality. This pathology is explained by the diversity of P. Falciparum strains and the variant allelic forms of parasite proteins that they produce. Cerebral malaria, a fatal form of the disease, is caused by the aggregation of infected red blood cells adhering to and blocking capillaries in the brain. Adults who have been exposed to variant strains of the P. Falciparum and are able produce a sufficient humoral response to parasite proteins involved in parasite cytoadherence. Children, however, have not been immunologically exposed to this diverse body of parasite proteins. Their inability to mount a strong immune response to variant strains can, in extreme situations, result in fatality. Antigenic diversity of parasite strains is a product of genetic recombination during both the sexual, vector phase and the asexual amplification phase during human red blood cell infection.



Individual Parasite Diversity

Antigenic diversity at the level of the individual parasite occurs during the course of infection of a given individual. Variation occurs in the surface antigens of infected red blood cells during the erythocytic schizogany phase of the parasite life cycle. The sequestration of the malaria parasites in human red blood cells during this phase of the cycle poses an extremely complex method for evasion to the host immunity. First, infected RBCs do not induce CTL response due to their lack


Courtesy Sanger Center

of MHC expression. Second, parasite derived particles exposed on the surface of the cell are highly variable, leading to the inability of the immune response to produce adequate memory to the antigens. These molecules are associated with PfEMP-1 proteins and undergo high clonal variation (2% per generation, in culture).



Figure adapted from Dr. Tilley, La Trobe University


These proteins are produced by the parasite within the infected red blood cell, and are transported to the cell surface. At the surface PfEMP-1 becomes associated with Histidine-Rich Proteins (HRP) to form knob-like protrusions at the membrane. PfEMP-1 is responsible for infected erythrocyte adherence. The genes coding for PfEMP-1 have been characterized as the var genes, and are found on a number of the parasite’s fourteen chromosomes. Individual parasite genomes contain a diverse repertoire of 50-150 var genes. Because only a limited number of the genes are expressed by each parasite, switches between different loci of the gene during asexual reproduction can lead to the production of extremely diverse PfEMP-1 proteins amongst the population. This variation is immunologically important as it results in the host’s inability to produce appropriate antibodies within the limited time frame of erythrocyte infection. The specific mechanism of the gene expression regulation has not been determined.


Links to other malaria sites

Brown Bio 160 page on malaria
The Sanger Center--Plasmodium falciparum Genome Project
World Health Organization, Division of Control of Tropical Diseases (malaria)
NCBI: Malaria Genetics & Genomics
Parasite Databases of Clustered ESTs
TIGR Parasites Database



Sources

Deitsch KW, Moxon RE, Wellems TE: Shared themes of antigenic variation and virulence in bacterial, protozoal and fungal infections. Microbiology and Molecular Biology Reviews 61: 281-293, 1997.
Hommel M. 1985. Antigenic Variation in Malarial Parasites. Immunology Today. 6:28-33.
Ramasamy R. 1998. Molecular basis for evation of host immunity and pathogenesis in malaria. Biochimica et Biophysica Acta. 1406:10-27.
Roberts DJ, Craig AG, Berendt AR, Pinches R, Nash G, Marsh K, Newbold CI. 1992. Rapid switching to multiple antigenic and adhesive phenotypes in malaria. 357:689-92.
Rogerson SJ, et al. 1995. Chondroitin sulfate A is a cell surface receptor for Plasmodium falciparum-infected erythrocytes. J Exp Med. 182:15-20.
Su XZ, Heatwole VM, Wertheimer SP, Guinet F, Herrfeldt JA, Peterson DS, Ravetch JA, Wellems TE. 1995. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell. 82:89-100