Date Published: September 5, 2019
Publisher: Public Library of Science
Author(s): Hirdesh Kumar, Niraj H. Tolia, Audrey Ragan Odom John.
Sporozoites are deposited into the dermis of the host upon the bite of an infected mosquito. These motile sporozoites traverse through the skin to find blood vessels and subsequently reach the liver through the circulatory system. Before a sporozoite can invade and replicate in a hepatocyte, it must traverse several physical barriers, including fibroblasts, Kupffer cells, and sinusoidal endothelial cells, to reach the target hepatocyte. Host cell traversal is the process of parasite entry into, passage through, and egress from host cells without lysis. Host cell traversal protects the vulnerable sporozoite from phagocytosis, primes the sporozoite through the activation of apical exocytosis, and prepares the motile sporozoite for invasion . In addition, the release of hepatocyte growth factor during sporozoite traversal enhances the infection rate of neighboring cells. Plasmodium uses stage-specific pore-forming proteins to disrupt host cell membranes to either enter or exit host cells during traversal, and to egress from the parasite-built parasitophorus membrane after invasion and replication. The characterized pore-forming proteins include sporozoite protein essential for cell traversal 1 (SPECT1), perforin-like proteins (PLPs), and cell traversal protein for ookinetes and sporozoites (CelTOS) (Fig 1A).
Following initial cell traversal, migratory sporozoites establish hepatocyte infection and undergo exponential growth to develop tens of thousands of primary merozoites. During active invasion, sporozoite surface proteins interact with host receptors to facilitate entry into the host cell. The three most actively studied sporozoite surface coat proteins are circumsporozoite protein (CSP), thrombospondin-related adhesive protein (TRAP), and P36 (Fig 1B).
Primary merozoites released from ruptured hepatocytes enter into the blood stream, invade erythrocytes, and develop into ring, trophozoite, and schizont stages, culminating in the formation of 16 to 32 mature merozoites. Each of these merozoites can invade a fresh erythrocyte and continue the cyclic, asexual blood stage development. Malaria parasites also exhibit distinct red cell tropism with P. falciparum invading reticulocytes as well as mature erythrocytes, while P. vivax is specific for reticulocytes.