No abstract

SummaryOur previous morphological studies illustrated the association of sterols with Plasmodium infecting hepatocytes. Because malaria parasites cannot synthesize sterols, they must scavenge these lipids from the host. In this paper, we have examined the source/s of sterols for intrahepatic Plasmodium and evaluated the importance of sterols for liver stage development. We show that Plasmodium continuously diverts cholesterol from hepatocytes until release of merozoites. Removal of plasma lipoproteins from the medium results in a 70% reduction of cholesterol content in hepatic merozoites but these parasites remain infectious in animals. Plasmodium salvages cholesterol that has been internalized by low-density lipoprotein but reduced expression of host low-density lipoprotein receptors by 70% does not influence liver stage burden. Plasmodium is also able to intercept cholesterol synthesized by hepatocytes. Pharmacological blockade of host squalene synthase or downregulation of the expression of this enzyme by 80% decreases by twofold the cholesterol content of merozoites without further impacting parasite development. These data enlighten that, on one hand, malaria parasites have moderate need of sterols for optimal development in hepatocytes and, on the other hand, they can adapt to survive in cholesterol-restrictive conditions by exploitation of accessible sterols derived from alternative sources in hepatocytes to maintain proper infectivity.

Malaria parasites encounter diverse conditions as they cycle between their vertebrate host and mosquito vector. Within these distinct environments, the parasite undergoes drastic transformations, changing both its morphology and metabolism. Plasmodium species that infect mammals must first take up residence in the liver before initiating red blood cell infection. Following penetration into hepatocytes, the parasite converts from an invasion-competent, motile, elongated sporozoite to a metabolically active, round trophozoite. Relatively little is known about the cellular events involved in sporozoite metamorphosis. Our data uncover the early cellular events associated with these transformations. We illustrate that the beginning of metamorphosis is marked by the disruption of the membrane cytoskeleton beneath the plasma membrane, which results in a protruding area around the nucleus. As this bulbous region expands, the two distal ends of the sporozoite gradually retract and disappear, leading to cell sphericalization. This shape change is associated with major interior renovations and clearance of superfluous organelles, e.g. micronemes involved in invasion. The membrane cytoskeleton is reorganized into dense lamellar arrays within the cytoplasm and is partially expulsed by converting parasites. Simultaneously, micronemes are compartmentalized into large exocytic vesicles and are then discharged into the environment. At the completion of metamorphosis, the parasites only retain organelles necessary for replication. These observations lay the groundwork for further investigations on the developmental pathways implicated in the metamorphosis of the malaria parasite.