More recently it has been demonstrated that a distinct subset of var genes are highly transcribed following selection on human brain endothelial cells and that these same distinct subtypes are associated with cerebral malaria (Aird 2014; Cunnington 2013; Smith 2013). This tissue specific expression of particular var genes implies that different tissues are selecting out different parasite populations based on the particular PfEMP1 being expressed on the surface of the infected erythrocyte.
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 response by expressing antigenically distinct PfEMP1 molecules on the erythrocyte surface. This allows the parasite to avoid clearance by the host immune system, but yet maintain the cytoadherent phenotype. This antigenic switching may occur as frequently as 2% per generation in the absence of immune pressure (Roberts 1992). The molecular mechanism of antigenic switching is not known. Experimental evidence indicates that the mechanism is not associated with duplicative transposition 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 proteins which bind to the promoter region. A gene can become activated by repositioning to a particular location in the nucleus and is associated with chromatin modification. This expression spot can only accommodate a single active gene promoter. Thus the var promoter is sufficient for both the silencing and the mono-allelic transcription of a PfEMP1 allele (Voss 2006; Guizetti 2013).
Summary
- The malarial parasite modifies the erythrocyte by exporting proteins into the host cell.
- One such modification is the expression of PfEMP1 on the erythrocyte surface which functions as the cytoadherent ligand.
- The binding of this ligand to receptors on host endothelial cells promotes sequestration and allows the infected erythrocyte to avoid the spleen.
- Numerous PfEMP1 genes (i.e., the var gene family) provide the parasite with a means to vary the antigen expressed on the erythrocyte surface.
- This antigenic variation also correlates with different cytoadherent phenotypes.