The hemoglobins S and C protect carriers from severe Plasmodium falciparum malaria. Here, we found that these hemoglobinopathies affected the trafficking system that directs parasite-encoded proteins to the surface of infected erythrocytes. Cryoelectron tomography revealed that the parasite generated a host-derived actin cytoskeleton within the cytoplasm of wild-type red blood cells that connected the Maurer's clefts with the host cell membrane and to which transport vesicles were attached. The actin cytoskeleton and the Maurer's clefts were aberrant in erythrocytes containing hemoglobin S or C. Hemoglobin oxidation products, enriched in hemoglobin S and C erythrocytes, inhibited actin polymerization in vitro and may account for the protective role in malaria.

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Besides its well-established role in generating COPI vesicles by recruiting coatomer at the Golgi, the small GTPase ARF1 is additionally involved in the formation of anterograde and retrograde tubular carriers at the Golgi.

by guest on July 10, 2020 http://www.jbc.org/ Downloaded from Figure 1. Continuous in vitro culture of B. duncani in hamster RBCs and transfer to human RBCs. A, parasitemia expressed as the percentage of hamster RBCs infected by the parasite at 1, 2, and 3 days post-inoculation (DPI) in a representative experiment. Columns represent mean Ϯ S.E. (error bars) of six biological replicates. B, micrograph of the intracellular development of cultured B. duncani in hamster RBCs in a Giemsa-stained smear prepared at 3 days post-inoculation. The parasitemia was 15% in this sample. C, transfer of B. duncani to human RBCs. B. duncani-infected hamster RBCs (haRBCs) were freshly harvested and maintained in culture in the presence of human RBCs (hRBCs). Left, free merozoites and infected haRBCs. Right, successful development of B. duncani in hRBCs. Human RBCs are distinguishable from haRBCs by their larger size and darker staining. ACCELERATED COMMUNICATION: In vitro culture of B. duncani

SummaryThe haemoglobinopathies S and C protect carriers from severe Plasmodium falciparum malaria. We have recently shown that haemoglobin S and C interfere with host-actin remodelling in parasitized erythrocytes and the generation of an actin network that seems to be required for vesicular protein trafficking from the Maurer's clefts (a parasite-derived intermediary protein secretory organelle) to the erythrocyte surface. Here we show that the actin network exerts skeletal functions by anchoring the Maurer's clefts within the erythrocyte cytoplasm. Using a customized tracking tool to investigate the motion of single Maurer's clefts, we found that a functional actin network restrains Brownian motion of this organelle. Maurer's clefts moved significantly faster in wild-type erythrocytes treated with the actin depolymerizing agent cytochalasin D and in erythrocytes containing the haemoglobin variants S and C. Our data support the model of an impaired actin network being an underpinning cause of cellular malfunctioning in parasitized erythrocytes containing haemoglobin S or C, and, possibly, for the protective role of these haemoglobin variants against severe malaria.