Ability of Plasmodium falciparum to invade Southeast Asian ovalocytes varies between parasite lines

Abstract

IntroductionInvasion of host red blood cells (RBCs) by the merozoite is a pivotal step in the life cycle of the malaria parasite Plasmodium falciparum and a clear target for vaccine development. The process of invasion is complex and involves multiple ligand-receptor interactions that are still poorly understood. Additional complexity of this process comes from the heterogeneity among P falciparum lines in the use of particular receptors, as demonstrated by experiments with enzyme-treated and mutant RBCs. 1,2 Malaria is presumed to be the single infectious disease that has had the biggest impact on the human genome, with some genetic traits maintained at relatively high frequencies in malaria endemic populations because of the selective advantage that they confer against this disease. 3 Many of these polymorphisms involve proteins that are expressed in the RBC, including hemoglobin and proteins located at the surface of RBCs. However, it is not completely clear yet whether any of these polymorphisms confers a selective advantage against malaria by preventing invasion by P falciparum merozoites.Southeast Asian ovalocytosis (SAO) is a peculiar RBC abnormality that results from a 27-bp deletion in the gene encoding band 3 (AE1⌬27), 4 the major transmembrane protein in the RBC. Band 3 has a cytoplasmic N-terminal domain and a C-terminal domain with 12 or 14 membrane-spanning regions. 5 This protein functions as an anion transporter but also has a role in maintaining the integrity of the RBC by anchoring the membrane to the underlying cytoskeleton. The 9-amino acid deletion that defines the SAO trait is located at the boundary between the cytoplasmic domain and the first transmembrane segment and results in major alterations in the folding and function of the membrane domain. 6-9 The SAO trait is found only in the heterozygous state and is presumed to be lethal when homozygous, 10 but the presence of mutated band 3 has dominant effects. The mutant band 3 induces conformational changes in essentially all of the normal fraction of the protein, 7 which is explained by the predominance of band 3 heterotetramers, higher order hetero-oligomers, and aggregates in SAO RBCs, in contrast to normal RBCs where band 3 is mainly found as dimers. 7,11,12 SAO RBCs are deficient in anion transport 9 and their mechanical properties are also dramatically altered. These RBCs are oval in shape and exhibit reduced cell deformability and an extreme increase in membrane rigidity. [13][14][15] Furthermore, mutant band 3 results in a decrease in the expression of several RBC antigens. 8,16 SAO also has an effect on susceptibility to malaria. Despite lethal selection against homozygous SAO carriers, this trait reaches high prevalence in some parts of the Western Pacific, 17 and the prevalence of this trait correlates with malaria endemicity in Papua New Guinea (PNG). 10 Two independent epidemiologic studies demonstrated that the SAO trait confers a striking protection against cerebral malaria, 18,19 one of the most devastating complications of...

Minimal Association of Common Red Blood Cell Polymorphisms with Plasmodium falciparum Infection and Uncomplicated Malaria in Papua New Guinean School Children

“…3,12,15 Earlier studies have showed reduced invasion or growth rates of P. falciparum in RBC from donors carrying SAO and GYPCDex3 . 13,14 The ability of P. falciparum to use different invasion pathways, redundancy in the erythrocyte invasion ligands used by P. falciparum , 29 and the earlier observation that only one of four EBA140/BAEBL variants (VSTK) failed to bind to Gerbich-negative erythrocytes, 30 could explain why the expected partial abrogation of the EBA140/BAEBL-GYPC invasion pathway by GYPCDex3 was observed to have little effect on infection rates or parasitemias in vivo . Whereas results from in vitro studies suggest that only a subset of parasite variants can invade SAO RBCs, those that can invade, do so efficiently.…”

“…13,14 However, cross-sectional and case-control studies have so far not found any significant associations between SAO or GYPC genotypes and prevalence or density of P. falciparum infections. 3,12,15 To date, no longitudinal studies, which are less prone to bias and confounding factors, have been performed on either polymorphism and no studies investigating the role of GYPCDex3 and symptomatic malaria have been reported.…”

Transcriptional variation in the malaria parasitePlasmodium falciparum

“…Expression of alternative members of these families, possibly with different functional abilities, has the potential to mediate adaptation to changes in host metabolic/nutritional conditions, changes in temperature associated to febrile episodes, or host genetic polymorphism in erythrocyte receptors, respectively, which are probably the major fluctuating environmental conditions that P. falciparum asexual stages face beyond immune pressure (Merrick and Duraisingh 2010). Importantly, two of the transcriptionally different parasite lines characterized in this study differ in their ability to use alternative invasion pathways or to invade erythrocytes with the cerebral malaria-protective mutation SAO (Cortés et al 2004), and here we provide evidence that some of the parasite lines also differ in their sensitivity to heat-shock. Also supporting the idea that variant expression can modulate fitness and hence permit adaptation upon challenge, switches in the expression of clag3 genes were recently shown to result in altered sensitivity to chemical inhibitors (Nguitragool et al 2011) and may determine changes in solute permeability.…”

“…3D7 stocks 3D7-A and 3D7-B, and 3D7-A subclones have also been described before (Cortés et al 2004(Cortés et al , 2007Cortés 2005). HB3A and HB3B are stocks of the same HB3 clonal parasite line obtained before (HB3A) or after (HB3B) mosquito and chimpanzee passage (Walliker et al 1987), kindly provided by O. Kaneko (Nagasaki University, Japan).…”

“…After excluding these genes to focus only on epigenetic transcriptional variation, we generated a list of 138 genes that we called the ''3D7 variantome'' (Supplemental Table S1), defined as the set of genes with clonally variant expression in 3D7. Some of these genes (76 of 138) belong to the large hypervariable families var, rif, stevor, and pfmc-2tm (Sup- (Cortés et al 2004). 7G8 subclones were identified as self-fertilization events after passage through mosquito and splectomized chimpanzee (Hayton et al 2008).…”