The extensive redundancy in the use of invasion ligands by Plasmodium falciparum, and its unique ability to switch between invasion pathways have hampered vaccine development. P. falciparum strains Dd2 and W2mef have been shown to change from sialic acid (SA)-dependent to SA-independent phenotypes when selected on neuraminidase-treated erythrocytes. Following an observation of increasing ability of Dd2 to invade neuraminidase-treated cells when cultured for several weeks, we systematically investigated this phenomenon by comparing invasion phenotypes of Dd2, W2mef and 3D7 strains of P. falciparum that were cultured with gentle shaking (Suspended) or under static (Static) conditions. While Static Dd2 and W2mef remained SA-dependent for the entire duration of the investigation, Suspended parasites spontaneously and progressively switched to SA-independent phenotype from week 2 onwards. Furthermore, returning Suspended cultures to Static conditions led to a gradual reversal to SA-dependent phenotype. The switch to SA-independent phenotype was accompanied by upregulation of the key invasion ligand, reticulocyte-binding homologue 4 (RH4), and the increased invasion was inhibited by antibodies to the RH4 receptor, CR1. Our data demonstrates a novel mechanism for inducing the switching of invasion pathways in P. falciparum parasites and may provide clues for understanding the mechanisms involved.

We have identified and functionally characterized a novel Plasmodium falciparum surface-related antigen (PfSRA) as a potential multistage vaccine candidate. The antigen is localized on both merozoites and gametocytes with high anti-PfSRA growth inhibition assay activity in laboratory strains and clinical isolates.

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the central role that erythrocyte invasion plays in Plasmodium falciparum survival and reproduction makes this process an attractive target for therapeutic or vaccine development. However, multiple invasion-related genes with complementary and overlapping functions afford the parasite the plasticity to vary ligands used for invasion, leading to phenotypic variation and immune evasion. Overcoming the challenge posed by redundant ligands requires a deeper understanding of conditions that select for variant phenotypes and the molecular mediators. While host factors including receptor heterogeneity and acquired immune responses may drive parasite phenotypic variation, we have previously shown that host-independent changes in invasion phenotype can be achieved by continuous culturing of the W2mef and Dd2 P. falciparum strains in moving suspension as opposed to static conditions. Here, we have used a highly biologically replicated whole transcriptome sequencing approach to identify the molecular signatures of variation associated with the phenotype switch. The data show increased expression of particular invasion-related genes in switched parasites, as well as a large number of genes encoding proteins that are either exported or form part of the export machinery. The genes with most markedly increased expression included members of the erythrocyte binding antigens (EBA), reticulocyte binding homologues (RH), surface associated interspersed proteins (SURFIN), exported protein family 1 (EPF1) and Plasmodium Helical Interspersed Sub-Telomeric (PHIST) gene families. the data indicate changes in expression of a repertoire of genes not previously associated with erythrocyte invasion phenotypes, suggesting the possibility that moving suspension culture may also select for other traits.Plasmodium falciparum malaria remains a major global public health challenge 1-3 . The 48-hour cyclical asexual replication of the blood stage parasite is responsible for the clinical symptoms of the infection 4 . Parasite control is hampered by genetic and phenotypic variations that impact negatively on drug and vaccine development strategies. Thus, a better understanding of the molecular mechanisms responsible for parasite phenotypic variation is important for the development and application of new malaria control strategies.Erythrocyte invasion by P. falciparum merozoites has been a subject of significant research interest due to its central role in parasite survival and transmission 5-7 . Some of these studies have demonstrated the importance of invasion-related gene families in the parasite genome, particularly the erythrocyte binding antigens (EBAs) and reticulocyte binding-like homologues (RHs) 5,8-16 . The array of different genes involved in invasion allows the parasite to vary ligands used for invasion [17][18][19][20] , enabling adaptation to differences in host environments including erythrocyte receptor heterogeneity and ligand-specific immune responses [21][22][23][24][25] . Expression and usage of particular ligands appear to depe...

Malaria remains a major cause of childhood deaths in resource-limited settings. In the absence of an effective vaccine, drugs and other interventions have played very significant roles in combating the scourge of malaria. The recent reports of resistance to artemisinin necessitate the need for new antimalarial drugs with novel mechanisms of action. Towards the development of new, affordable and easily accessible antimalarial drugs for endemic regions, the Medicines for Malaria Venture (MMV) assembled a total of 400 active antimalarial compounds called the Malaria Box. The potency and the efficacy of the Malaria Box Compounds have been determined mainly using laboratory strains of P. falciparum.This study investigated the potency of twenty compounds from the Malaria Box against four clinical isolates from Ghana, using optimized in vitro growth inhibitory assays. Seven out of the 20 compounds screened had 50% inhibitory concentration (IC50) below 500 nM. The most active among the selected compounds was MMV006087 (average IC50 of 30.79 nM). Variations in the potency of the Malaria Box Compounds were observed between P. falciparum clinical isolates and Dd2 strain. We also investigated the sensitivity of the clinical isolates to chloroquine and artesunate. The N093 clinical isolate was found to be resistant to chloroquine but showed high sensitivity to artesunate.The results underscore the importance of including clinical isolates with different drug-resistant backgrounds, in addition to laboratory strains, in validating potential compounds during antimalarial compound screening programs.