[Plasmodium sporozoite entry pathways during malaria liver infection]. / Phase hépatique du paludisme : voies d'entrée des sporozoïtes de Plasmodium.

ABSTRACT

Plasmodium parasites, the causative agents of malaria, are transmitted by female Anopheles mosquitoes, which inject sporozoites into the skin of the host. The motile sporozoites enter the blood stream and, upon reaching the liver, transform into liver stages inside hepatocytes. The parasites enter host cells actively, using their actomyosin motor machinery to propel themselves through a specialized structure called junction. Penetration inside an invagination of the host cell plasma membrane results in the formation of the parasitophorous vacuole, which is essential for parasite further development. The mechanisms of sporozoite entry into host cells remain poorly understood at the molecular level. We reported for the first time a host factor required for infection of hepatocytes by Plasmodium sporozoites, the tetraspanin CD81, which also serves as a receptor for the hepatitis C virus. CD81 is involved at an early step of the infection, however no evidence for a direct interaction between CD81 and the parasite could be found. Although sporozoites can use several independent pathways to enter hepatocytes, depending on the parasite species and the host cell type, we showed that P. falciparum, the deadliest human malaria parasite, depends on CD81 to infect hepatocytes. We identified structural determinants in the CD81 large extracellular domain, and demonstrated that CD81 function is regulated by its molecular environment in specialized tetraspanin-enriched membrane microdomains. Based on these data we propose that CD81 acts indirectly during malaria infection, by interacting with other essential but still unidentified factor(s), possibly a receptor for the sporozoites, within specific microdomains of the hepatocyte plasma membrane.