Figure 5.

Proposed model for CelTOS-mediated pore formation (1). Prepore CelTOS exists as dimer on parasite surface. The engineered disulfide linkages (S–S) and single proline to alanine mutation (P117A) stabilize the dimer state (shown in blue panel) (2). Inside the host cell, interaction between phosphatidic acid (PA)–bound CelTOS (A) and cell membrane leads to conformational rearrangement in CelTOS and penetration into the membrane (B). C, membrane-inserted dimer dissociates into two monomers and forms prepore in the cell membrane. D, prepore states lead to generation of the mature pore. Small-molecule inhibitors may target CelTOS at all stages, whereas antibodies may be effective at extracellular stages of CelTOS. CelTOS is localized on the Plasmodium surface of the extracellular parasite and forms pores at the inner leaflet of the host cell to disrupt the host cell membrane to enable parasites to exit the host cell (9). Protective CelTOS-specific antibodies may function by binding to the extracellular stages of the prepore CelTOS states facilitating parasite recognition and clearance or by binding to the extracellular face of the mature CelTOS pore facilitating infected-cell recognition and clearance. In contrast, small-molecule inhibitors that target any state of CelTOS for inhibition of activity may also prove effect in preventing malarial infection or transmission. CelTOS, Cell-traversal protein for ookinetes and sporozoites.