Malaria Parasite¶s Immune Evasion

Introduction
³Malaria parasites are major human pathogens annually associated with 300 million to 500 million clinical cases worldwide and 0.5 million to 3 million deaths, mostly among children under the age of 5 years living in sub-Saharan Africa´ (Carter). Malaria is caused by a blood borne infection by protozoan parasites of the genus Plasmodium, which are transmitted from one human to another by female Anopheles mosquitoes. Four species of the plasmodium parasite can infect humans (Fig.1): the most serious forms of the disease are caused by Plasmodium falciparum. Malaria caused by Plasmodium vivax, Plasmodium ovale and Plasmodium malariae cause milder disease in humans that is not generally fatal. Molecular genetics reveal that P. falciparum is very closely related to malaria parasites of chimpanzees; while the three remaining species of human malaria parasite: P. malariae, P. ovale, and P. vivax fall under a single clade that includes all mammalian malaria parasites. P. falciparum, causes the most severe infections and nearly all malaria-related deaths, and has been characterized in areas of high endemicity in Africa. In my poster discussion I am going to focus on the P. falciparum strain of malaria, specifically looking at various antigen binding proteins and concluding with future potential therapeutic strategies derived from these various antigen binding receptors. There is a great diversity of malarial surface antigens which is one of the main reasons why clinical immunity develops only after repeated infections with the same species over several years. Antigenic diversity has a dual origin. One is the classical genetic mechanism of nucleotide replacement and recombination that creates polymorphism, the existence of genetically stable alternative forms of antigen-coding genes. The second mechanism is antigenic variation. This is a clonal lineage of parasites which express successively alternate forms of an antigen without changes in genotype. Previous studies conclude that the malaria parasite P. falciparum utilizes molecules present on the surface of unifected red blood cells for rosette formation. Rosetting formation is clusters consisting of a cell (usually a lymphocyte) surrounded by antigenic cells. The rosette-forming cell may be an antibody-forming cell, a memory cell, a t-cell, or a cell bearing surface cytophilic antibodies. Rosette formation can be used to identify specific populations of these cells. ³The P. falciparum erythrocyte membrane protein 1 (PfEMP1), a member of a family of high-molecular-weight polypeptides encoded by the var genes, has been identified as a rosetting ligand. Various host receptors on the surface of uninfected RBC have been proposed, including ABO blood group antigens, CD36, CD35, and heparan sulfate (HS) or HS-like molecules´ (Barragan). However there is no evidence about the contribution of different receptors in rosetting and there natural states. This study focused on the utilization of ABO blood group antigens for rosette formation. Clinical isolates were used to emphasize the antirosetting effect of hyperimmune sera in relation to the ABO blood group and to examine the relationship of A antigen to the rosetting phenotype.

TABLE 2. Relative rosette-forming capacities of blood group A and blood group O RBC

Conclusion
‡ Earlier data suggests that glycans are common rossetting receptors in many P.falciparum strains ‡ Data from study suggests that all P.falciparum strains have the potential to use another receptor confined to ABO blood group system ‡ Results show influence of ABO blood group type on rosetting ‡ Red blood cell polymorphisms also affect rosette formation ‡ Differences in antirosetting effect of immune sera between isolates from group O hosts and group A and B hosts reflect differences in strength of rosetting binding mechanism ‡ Show that A and B antigens are determinants for rosetting in P. falciparum ‡ Evidence for two different acting receptors for PfEMP1-mediated rosetting ‡ P. falciparum chooses different glycan interactions with the red blood cell surface for rosetting ‡ Approach for creating vaccine must focus on rosetting ligand providing multiple targets where blood group preference of the parasite in combination with blood group of that patient may be determinant factors

FIG. 1. Phylogeny of the malaria parasites of humans and of some other related malaria parasite species.

References
FIG. 2. Rosette
disruption by immune sera in relation to ABO blood group. Nine samples of immune serum from healthy individuals, six of blood group A and three of blood group B, were tested for antirosetting activity on isolates from hosts of blood group A, B, or O. Antirosetting activity (percent inhibition of rosetting) is depicted in a five-level grey scale as indicated. Two serum samples from nonimmune Swedes (ni1 and ni2) were used as controls. Barragan, Antonio. Kremsner, Peter G.Wahlgren, Mats and Carlson, Johan. Blood Group A Antigen Is a Coreceptor in Plasmodium falciparum Rosetting. Infect Immun. 2000 May; 68(5): 2971-2975. Carter, Richard and Mendis, Kamini N. . Evolutionary and Historical Aspects of the Burden of Malaria. Clin. Microbiol. Rev., Oct 2002; 15: 564 - 594.

FIG. 3. Binding of A antigen to surfaces of parasite-infected erythrocytes. (A) A antigen conjugate was allowed to bind to a living culture. The pRBC were counterstained with ethidium bromide and visualized by UV microscopy. (B) Sensitivity of rosetting and A antigen conjugate binding by pRBC of FCR3S1 cultures to trypsin treatment as indicated in Materials and Methods. (C) Competition of A antigen conjugate binding to living cultures by A-trisaccharide and Hdisaccharide. All results shown are means SDs (error bars) from three separate experiments.

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