Cells infected by malaria parasites without SBP1 (right) align membranes poorly.

When the malaria parasite Plasmodium falciparum infects red blood cells (RBCs), it makes a protein called PfEMP1 that is displayed on the RBC surface. PfEMP1 sticks the RBCs to vessels walls; those immobilized cells can then block small blood vessels and produce malaria symptoms.

Now, Cooke et al., on page 899, show that knocking out a single gene in P. falciparum prevents transport of PfEMP1, the parasite's major virulence factor, to the outer surface of the plasma membrane of infected RBCs.

PfEMP1 and numerous other Plasmodium proteins travel to the plasma membrane via parasite-constructed membranous structures called Maurer's clefts. The clefts dock under the surface of the plasma membrane and deposit several parasite proteins.

Cooke et al. found that knocking out skeleton binding protein-1 (SBP1), a resident of clefts, blocked PfEMP1 from reaching the RBC surface. Without that protein, the infected RBCs failed to latch onto the surface of the surrounding endothelium as infected cells normally do. Transport of the other virulence proteins to the cytoskeleton was normal in the mutants, and even PfEMP1 made it as far as the Maurer's cleft.

It is not clear how SBP1 normally ferries PfEMP1 across the membrane. Biochemical and immunoprecipitation experiments showed that the two proteins were not in direct contact. However, in RBCs infected with the mutant parasite, the Maurer's clefts never got quite as close to the membrane as they did in wild-type infected cells. Therefore, SBP1 may help pull the two membranes toward one another in some unknown way.

Malaria parasites carry as many as 76 PfEMP1 genes and switch expression of them regularly to escape the host immune system. Significantly, knocking out the single SBP1 gene prevented transport of all varieties of PfEMP1 tested thus far. The team, along with several collaborators, has already started a rational drug design approach to develop an inhibitor of SBP1.