Plasmodium falciparum, the causative agent of the most lethal form of human 
malaria, uses multiple ligand-receptor interactions to invade host red blood 
cells (RBCs). We studied the invasion of P falciparum into abnormal RBCs from 
humans carrying the Southeast Asian ovalocytosis (SAO) trait. One particular 
parasite line, 3D7-A, invaded these cells efficiently, whereas all other lines 
studied invaded SAO RBCs to only about 20% of the extent of normal (non-SAO) 
cells. This result is consistent with the clinical observation that SAO 
individuals can experience high-density P falciparum infections and provides an 
explanation for previous discrepant results on invasion of SAO RBCs. 
Characterization of the invasion phenotype of 3D7-A revealed that efficient 
invasion of SAO RBCs was paralleled by relatively efficient invasion of normal 
RBCs treated with either neuraminidase, trypsin, or chymotrypsin and a novel 
capacity to invade normal RBCs treated sequentially with both neuraminidase and 
trypsin. Our results suggest that only parasites able to use some particular 
invasion pathways can invade SAO RBCs efficiently in culture. A similar 
situation might occur in the field.