Erythrocytes carrying mutations in spectrin and protein 4.1 show differing sensitivities to invasion byPlasmodium falciparum

Abstract

The role of the erythrocyte skeleton in the invasion process of Plasmodium falciparum was evaluated using genetically variant erythrocytes containing well-defined molecular defects in alpha spectrin (alpha Sp) or protein 4.1 from eight unrelated families. Invasion into red cells from subjects of three black families with hereditary pyropoikilocytosis (HPP) due to inheritance of alpha I/74 mutant spectrin was significantly reduced in cells both from the patients and from the relatives of these who carried asymptomatic hereditary elliptocytosis (HE). Likewise, reduced invasion was also seen in red cells from two families with HE in which the alpha I/65 variant spectrin was present. Resistance to invasion was not absolute in any sample and varied between 38% and 71% of that seen in normal cells. The decreased invasion correlated with the percentage of spectrin dimers present within the membrane of variant cells. In contrast, invasion into elliptocytes from three families that had a partial deficiency in protein 4.1 (HE/4.1+) but a normal percentage of spectrin dimers was either unchanged or increased. The precise mechanism and molecular basis behind the reduced invasion into HPP and HE red cells bearing Sp alpha I domain variants remains to be elucidated but might relate to alterations in merozoite/red cell-receptor interactions and/or merozoite endocytosis. The occurrence of elliptocytosis with spectrin defects (in particular, Sp alpha I/65 and Sp alpha I/46 variants in West Africa) suggests that these mutations of the alpha Sp gene could be related to some protection against malaria.

New antimalarial indolone-N-oxides, generating radical species, destabilize the host cell membrane at early stages of Plasmodium falciparum growth: role of band 3 tyrosine phosphorylation

“…Indeed, erythrocytes with naturally unstable membranes (e.g., hereditary spherocytosis, hereditary pyropoikilocytosis, hereditary elliptocytosis, Asian ovalocytosis) do not support Plasmodium proliferation in vitro [32,37–40]. Furthermore, treatment of red cells with morphology-altering drugs has been shown to inhibit entry and maturation of the parasite in cell culture [41].…”

Common Host Variation Drives Malaria Parasite Fitness in Healthy Human Red Cells

“…We collected blood samples from 121 donors with no known history of blood disorders, most of whom self-identified as having recent African ancestry (Figure 1A). As a positive control, we also sampled a patient with hereditary elliptocytosis (HE), a polygenic condition characterized by extremely fragile RBC membranes that strongly inhibit P. falciparum growth (Schulman et al, 1990;Facer, 1995;Dhermy et al, 2007;Gallagher, 2013). We performed whole-exome sequencing (Figure 1-source data 1), both to check for the presence of known RBC disease alleles and to confirm the population genetic ancestry of our donors.…”

A novel ENU-induced ankyrin-1 mutation impairs parasite invasion and increases erythrocyte clearance during malaria infection in mice

“…Plasmodium relies on a favourable host environment in order to thrive, many erythrocyte-related polymorphisms have been discovered that interfere with parasite survival thus contributing to malaria resistance. These include polymorphisms that affect the cytoskeleton of erythrocytes, such as Southeast Asian Ovalocytosis (SAO), hereditary elliptocytosis (HE) and spherocytosis (HS)910111213. Several hypotheses have been proposed for the mechanisms by which they confer malaria protection, including reduced erythrocyte invasion, intra-erythrocytic growth and cytoadherence813141516171819.…”

“…However, due to the heterogeneity of the manifestation of these disorders in the human population, contradicting evidences for resistance mechanisms has often been presented. A study done by Facer13 showed that only patients carrying certain spectrin mutations have impaired parasite invasion of red blood cells (RBC), but not others that also exhibited HE symptoms. A similar observation was reported by Chishti, et al 17, where individuals with defective protein 4.1 exhibited intra-erythrocytic growth inhibition, but not those with glycophorin C defects, despite the fact that both defects gave rise to HE.…”