Figure 1. Schematic illustrating the extracellular interactions involved in Plasmodium sporozoite migration and invasion.

Sporozoites are deposited in the skin of the host when an infected mosquito takes a blood meal, and move within the dermis by an active process known as gliding motility. Sporozoites recognize and traverse the vascular endothelium to enter the bloodstream where they are transported to the liver. (A) The abundant sporozoite surface protein, TRAP, which is essential for gliding motility, has been recently found to interact with αv-containing integrins in their extended active conformation displayed on the surface of host cells, and may be involved in cell host recognition events in the dermis. (B) Sporozoites are transported to the liver where they are arrested within the liver sinusoids: specialized capillary beds bordered by a highly porous epithelium which contain fenestrations that are clustered into structures known as sieve plates. Hepatocytes are not separated from the vascular endothelial cells by the usual basement membrane, but rather by a conspicuous gap known as the space of Disse that are occupied by stellate cells; the lumen of the sinusoid is patrolled by hepatic macrophages called Kupffer cells. Parasites are thought to be arrested in the liver by interactions between the abundant sporozoite surface protein CSP and unusually high levels of sulfated HSPGs displayed by stellate cells that protrude as tufts through the fenestrations in the sinusoid endothelium. The arrested sporozoite enters the liver parenchyma either by cell traversal of Kupffer cells, which appears to involve CD68, or by traversal of endothelial cells. Sporozoites then traverse through several hepatocytes, a process which requires the action of the sporozoite proteins SPECT1, SPECT2 and CelTOS. Eventually, sporozoites productively invade a hepatocyte requiring the parasite proteins P36 and P52, and the host receptors SR-BI, and/or CD81, and potentially EPHA2.