Until a few years ago the dogma was that mature erythrocytic stages of Plasmodium falciparum adhered to host endothelial cells but that earlier “ring” forms were not able to bind and so were seen in the peripheral circulation. This disappearing act of the parasite has been linked to severe disease. But the recent demonstration that ring forms of the parasite are able to cytoadhere (Pouvelle et al, Nat Med. 2000;6:1264-1268), confirming pathologic observations, raised the specter of completely cryptic blood-stage populations of parasites in humans.
From this earlier work it was clear that the molecule(s) responsible for ring-stage cytoadherence were not the same as that involved in binding of later stages, namely PfEMP1, which raised the question: what might be the parasite ligand for this interaction? In this issue, Douki and colleagues (page 5025) have extended their previous work, identifying the smaller of 2 molecules implicated in adhesion (RSP2) as a rhoptery-derived protein, RAP2. In doing so, they provide an explanation as to how newly infected erythrocytes are able to cytoadhere directly after invasion and have also provided a mechanism to explain the curious phenomenon of uninfected erythrocyte sequestration during malaria infection. Insertion of RSP2/RAP2 into seemingly uninfected erythrocytes may have a role in the development of malarial anemia, one of several clinical forms of severe malaria.
A number of important questions remain, particularly what the basis is of the association of ring-stage adhesion with chondroitin sulfate A (CSA) binding, often seen in placental malaria (Scherf et al, Cell Microbiol. 2001;3:125-131). The possibilities include the physical proximity in the P falciparum genome of RSP2/RAP2 and the subtelomeric region, containing genes that encode PfEMP1, and specific forms of RSP2/RAP2 in CSA-binding parasites. Further work will be needed to unravel the molecular mechanisms involved in ring-stage adhesion, but the results published in this issue make a significant contribution to efforts to decode the language of malaria parasite adhesion.
