Abstract
Proteases have been implicated in a variety of developmental processes during the malaria parasite lifecycle. In particular, invasion and egress of the parasite from the infected hepatocyte and erythrocyte, critically depend on protease activity. Although falcipain-1 was the first cysteine protease to be characterized in P. falciparum, its role in the lifecycle of the parasite has been the subject of some controversy. While an inhibitor of falcipain-1 blocked erythrocyte invasion by merozoites, two independent studies showed that falcipain-1 disruption did not affect growth of blood stage parasites. To shed light on the role of this protease over the entire Plasmodium lifecycle, we disrupted berghepain-1, its ortholog in the rodent parasite P. berghei. We found that this mutant parasite displays a pronounced delay in blood stage infection after inoculation of sporozoites. Experiments designed to pinpoint the defect of berghepain-1 knockout parasites found that it was not due to alterations in gliding motility, hepatocyte invasion or liver stage development and that injection of berghepain-1 knockout merosomes replicated the phenotype of delayed blood stage growth after sporozoite inoculation. We identified an additional role for berghepain-1 in preparing blood stage merozoites for infection of erythrocytes and observed that berghepain-1 knockout parasites exhibit a reticulocyte restriction, suggesting that berghepain-1 activity broadens the erythrocyte repertoire of the parasite. The lack of berghepain-1 expression resulted in a greater reduction in erythrocyte infectivity in hepatocyte-derived merozoites than it did in erythrocyte-derived merozoites. These observations indicate a role for berghepain-1 in processing ligands important for merozoite infectivity and provide evidence supporting the notion that hepatic and erythrocytic merozoites, though structurally similar, are not identical.
Highlights
Malaria, caused by parasites of the genus Plasmodium, continues to be a global health problem, causing significant morbidity and mortality in resource poor settings [1]
Sporozoites subsequently travel to the liver, where they invade and replicate in hepatocytes, eventually releasing the stage of the parasite that is infectious for red blood cells, termed merozoites
Proteases are among the enzymes that are essential for parasite survival and their functions range from invasion of red blood cells, to the breakdown of red cell hemoglobin, to the release of parasites from red cells
Summary
Malaria, caused by parasites of the genus Plasmodium, continues to be a global health problem, causing significant morbidity and mortality in resource poor settings [1]. Human infection begins with the injection of sporozoites into the skin where, using gliding motility, they find and enter the blood stream, carrying the parasites to the liver [2]. They invade hepatocytes and develop into exo-erythrocytic forms (EEFs), replicating to produce thousands of hepatic stage merozoites. Once mature, these liver stage merozoites bud from the infected hepatocytes and enter the blood stream in packets termed merosomes [3]. Fertilization occurs in the mosquito midgut and the parasite migrates across the midgut wall to form oocysts containing sporozoites that are released and invade the salivary glands to be injected
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