Differential signaling by two Plasmodium sporozoite adhesins mediates transmission of malaria parasites

Malaria parasites are transmitted in the form of Plasmodium sporozoites, highly motile cells that form in oocysts at the mosquito midgut and invade salivary glands. After transmission to the vertebrate host, sporozoites migrate in the skin and liver to enter and differentiate in hepatocytes. Sporozoite migration and invasion are mediated by surface adhesins which link the extracellular substrate to the actin-myosin motor, providing the force for gliding motility. Here we show that two adhesins, TRAP and TRP1, use different extracellular domains and distinct cytoplasmic signaling to mediate salivary gland invasion and gliding motility. The extracellular thrombospondin repeat (TSR) of TRP1 but not the TSR of TRAP is essential for gliding and transmission and the TSR of TRAP can only partially rescue TSR function in TRP1. Furthermore, the cytoplasmic domain of TRAP cannot replace the equivalent domain of TRP1, which is essential for gliding and salivary gland invasion. This suggests that sporozoites integrate signals through multiple essential outside-in signaling pathways to achieve migration and invasion.