AMA1 and MAEBL are important forPlasmodium falciparumsporozoite infection of the liver

Abstract

The malaria sporozoite injected by a mosquito migrates to the liver by traversing host cells. The sporozoite also traverses hepatocytes before invading a terminal hepatocyte and developing into exoerythrocytic forms. Hepatocyte infection is critical for parasite development into merozoites that infect erythrocytes, and the sporozoite is thus an important target for antimalarial intervention. Here, we investigated two abundant sporozoite proteins of the most virulent malaria parasite Plasmodium falciparum and show that they play important roles during cell traversal and invasion of human hepatocytes. Incubation of P. falciparum sporozoites with R1 peptide, an inhibitor of apical merozoite antigen 1 (AMA1) that blocks merozoite invasion of erythrocytes, strongly reduced cell traversal activity. Consistent with its inhibitory effect on merozoites, R1 peptide also reduced sporozoite entry into human hepatocytes. The strong but incomplete inhibition prompted us to study the AMA-like protein, merozoite apical erythrocyte-binding ligand (MAEBL). MAEBL-deficient P. falciparum sporozoites were severely attenuated for cell traversal activity and hepatocyte entry in vitro and for liver infection in humanized chimeric liver mice. This study shows that AMA1 and MAEBL are important for P. falciparum sporozoites to perform typical functions necessary for infection of human hepatocytes. These two proteins therefore have important roles during infection at distinct points in the life cycle, including the blood, mosquito, and liver stages.

Gliding motility powers invasion and egress in Apicomplexa

“…In Plasmodium spp., it was not possible to knockout AMA1 and RON4; however, the conditional depletion of P. berghei AMA1 (PbAMA1) and PfAMA1 caused a defect in merozoite invasion 139,140 and in the sealing of the parasitophorous vacuole at the end of invasion 140 . By contrast, the conditional depletion of PbAMA1 does not affect the entry of sporozoites 137,139 , but blocking the interaction of AMA1-RON2 with a 20-residue peptide -'R1 peptide' , which specifically binds AMA1 -inhibits hepatocyte invasion by P. falciparum sporozoites 141 . Moreover, the deletion of a distant PfAMA1 homologue, PfMAEBL, severely impairs hepatocyte invasion by P. falciparum sporozoites without having an effect on gliding motility 141 .…”

“…By contrast, the conditional depletion of PbAMA1 does not affect the entry of sporozoites 137,139 , but blocking the interaction of AMA1-RON2 with a 20-residue peptide -'R1 peptide' , which specifically binds AMA1 -inhibits hepatocyte invasion by P. falciparum sporozoites 141 . Moreover, the deletion of a distant PfAMA1 homologue, PfMAEBL, severely impairs hepatocyte invasion by P. falciparum sporozoites without having an effect on gliding motility 141 . This suggests that PfAMA1 and the homologue PfMAEBL are not fully redundant, but further work is required to determine whether they act together.…”

Main B‐cell epitopes of PvAMA‐1 and PvMSP‐9 are targeted by naturally acquired antibodies and epitope‐specific memory cells in acute and convalescent phases of vivax malaria

“…A hypothesis that explains these observations is linked to the localization of AMA‐1 and MSPs in parasites. Specifically, the presence of AMA‐1, also found on sporozoites, can allow a specific immune response to be induced, even in the absence of erythrocytic stages in the parasite. On the other hand, as MSP are located in merozoites, it is imperative to establish the presence of blood infection in order to induce higher levels of MSP‐specific antibodies.…”

“…found on sporozoites 56,57 , can allow a specific immune response to be induced, even in the absence of erythrocytic stages in the parasite. On the other hand, as MSP are located in merozoites, it is imperative to establish the presence of blood infection in order to induce higher levels of MSP-specific antibodies.…”

Plasmodium falciparumProtein Exported in Erythrocyte and Mechanism Resistance to Malaria

“…The second step is called reorientation, which is produced for vertical arrangement of apical secretory organelles, such as rhoptries and micronemes. This step is mediated by a protein called apical membrane Antigen-1 (AMA1), which seems to establish the apical interaction of the adhesins with the erythrocyte; it is the border point between the weak union that occurs in the initial contact with MSP1 and irreversible bonds that occur between microneme proteins and erythrocyte membrane proteins [21,22]. The third step is the tight-binding formation between various adhesins produced at the apical end of the parasite and its membrane receptors in the red blood cell, where the Duffy binding-like proteins (DBL) and reticulocyte binding proteins (RBP) bind.…”