Malaria parasite pre-erythrocytic infection: preparation meets opportunity

Abstract

For those stricken with malaria, the classic clinical symptoms are caused by the parasite's cyclic infection of red blood cells. However, this erythrocytic phase of the parasite's life cycle initiates from an asymptomatic pre-erythrocytic phase: the injection of sporozoites via the bite of a parasite-carrying Anopheline mosquito, and the ensuing infection of the liver. With the increased capabilities of studying liver stages in mice, much progress has been made elucidating the cellular and molecular basis of the parasite's progression through this bottleneck of its life cycle. Here we review relevant findings on how sporozoites prepare for infection of the liver and factors crucial to liver stage development as well as key host/parasite interactions.

Figure 1

Key events of the liver stage developmental program. (Left-to-Right) A highly infectious sporozoite travels to the liver within minutes, where it traverses through the endothelium, wounds several hepatocytes without invading them, and finally invades one hepatocyte. During invasion, the parasite forms a parasitophorous vacuole (gray) around itself, actively expels/disassembles invasion-related organelles, and dedifferentiates into a trophozoite. Infection by P. vivax also can produce a dormant “hypnozoite” form that can reactivate months or years later. Liver stage parasites consume the contents of the hepatocyte and extensively replicate their genome and organelles, which are segregated during schizogony into each of tens of thousands of merozoites. The parasite grows to a size approximately 10 times that of an uninfected hepatocyte. Late in schizogony, the PV membrane breaks down and merozoites are enclosed in vesicles called merosomes, which form from the hepatocyte’s plasma membrane. Merosomes are released into the liver sinusoid, enter the circulation and eventually burst in the lung microvasculature to release the merozoites. The approximate time required for each developmental stage in rodent and human malaria is noted.