**33. Summary**

30 Malaria Parasites

The different types of DBL domains and CIDR (discussed above) bind to different endothelial cell receptors[ 86,87].For example, DBL, which comprises the first domain, bind to many of the receptors associated with resetting. The binding of the CIDR to CD36 may account for the abundance of this particular binding phenotype among parasite isolates.[88]

The encoding of the cytoadherence ligand by a highly polymorphic gene family presents a paradox in that receptor/ligand interactions are generally considered highly specific. Interestingly, selection for different cytoadherent phenotypes result in a concomitant change in the surface antigenic type.[89] Similarly, examination of clonal parasite lines revealed that change in the surface antigenic type correlated with difference in binding to CD36 and ICAMI. For example, the parental line (A4) adhered equally well to CD36 and ICAMI, whereas one of the A4-derived clones (C28) exhibited a marked preference for CD36.[90] Binding to ICAMI was then reselected by panning the infected erythrocytes on ICAMI. All three parasite clones (A4, C28, C28-I) exhibited distinct antigenic types as demonstrated by

The expression of a particular PfEMPI will result in a parasite with a distinct cytoadherent phenotype and this may also affect pathogenesis and disease outcome. For example, binding to ICAM-I is usually implicated in cerebral pathology. Therefore, parasites expressing a PfEMPI which binds to ICAMI may be more likely to cause cerebral malaria. In fact, higher levels of transcription of particular *var* genes are found in cases of severe malaria as compared to uncomplicated malaria.[91] Similarly, a higher proportion of isolates which bind to CSA are obtained from the placenta as compared to the peripheral circulation of either pregnant women or children.[92] Furthermore, placenta malaria is frequently associated with higher levels of transcription of a particular var gene which binds CSA .[93] This phenomenon is not restricted to the placenta in that, there is a dominant expression of particular *var* genes in the various tissue.[94] This tissue specific expression of particular *var*  genes implies that different tissues are selecting out different parasite populations based on the particular PfEMPI being expressed on the surface of the infected erythrocyte. To CSA, CD36, or ICAM-I. infected erythrocyte were collected from the placenta, peripheral circulation of the mother, or peripheral circulation of the child. (designated as group 1-6) expressed in different tissues (brain, lung, heart and spleen) from 3 different patients. PM30 died of severe malaria anemia. PM32 was diagnosed with both cerebral malaria and severe

Although sequestration offers many advantages to the parasite, the expression of antigens on the surface of the infected erythrocyte provides a target for the host immune system. The parasite counters the host immune responses by expressing antigenically distinct *Pf*EMPI molecules on the erythrocyte surface. This allows the parasite to avoid clearance by the host immune system, but yet maintain the cetoadherent phenotype. This antigenic switching may occur as frequently as 2% per generation in the absence of immune pressure.[95] The molecular mechanism of antigenic switching is not known. Experimental evidence indicates that the mechanism is not associated with duplication into specific expression-linked sites as found in African trypanosomes. Only a single var gene is expressed at a time (i.e… allelic exclusion). The non-expressed genes are kept silent by protein which bind to the promoter region. A gene can become activated by repositioning to a particular location in the nucleus

**32. Antigenic variation** 

agglutination with hyper-immune sera.

anemia. PM55 was diagnosed with only cerebral malaria.

