Abstract
Excessive binding of Plasmodium falciparum-infected erythrocytes to the microvascular endothelium (cytoadherence) and to uninfected eryrthrocytes (rosetting) are regarded as key-events in the development of a severe malaria infection.
P. falciparum rosetting was confirmed to be associated with the development of cerebral malaria in The Gambia. It was also found that there is a lack of anti-rosetting activity in sera from children with severe malaria disease, establishing the importance of rosetting as a marker for a parasite prone to cause complicated malaria. The parasite makes use of serum proteins such as immunoglobulins and fibrinogen to acquire or improve its binding abilities to uninfected erythrocytes, but there seems to exist a variation in between strains. The binding of non-immune immunoglobulins and fibrinogen to the surface of the P. falciparum-infected erythrocytes causes the formation of a fibrillar structure which is connected to the ability to form rosettes. Further, polyclonal antibodies directed towards human immunoglobulins or fibrinogen could disrupt already formed rosettes.
The endothelial receptor PECAM-I/CD31 was shown to be a cytoadhesion receptor for P. falciparum. PECAM-I/CD31 is involved in endothelial-endothelial binding as well as leukocyte-endothelial binding. The adhesion of P. falciparum is mediated by domains 1-2, close to the leukocyte binding site. P.falciparum clones that were by micro-manipulation selected for the rosette formation ability and then tested for adhesion to a series of known P. falciparum receptors were found to be multi-adhesive, i.e. the PRBC recognise multiple host cell receptors.
The trypsin sensitivity of the high molecular weight surface exposed, P. falciparum erythrocyte membrane protein I (PfEMPI) was similar to the trypsin sensitivity of most binding features studied (rosetting, blood group A adhesion, CD36-binding, auto-agglutination and immunoglobulin-binding) except binding to human umbilical vein endothelial cells that was abolished only at higher trypsin concentrations. Taken together, this suggests that PfEMPI is the main mediator of P. falciparum adhesion, yet other parasite polypeptides, such as the low molecular weight rosettings, may play important roles. In this thesis several new adhesive phenotypes of P. falciparum have been identified that may play crucial roles in the process leading to severe, sometimes fatal, P. falciparum infection.
