Deletion of the rodent malaria ortholog for falcipain-1 highlights differences between hepatic and blood stage merozoites

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. © 2017 hopp et al.