Adaptations of the malaria parasite Plasmodium falciparum to sickle trait blood

The causative agent of malaria, Plasmodium spp., and the human host are engaged in an ongoing evolutionary arms race. The parasite invades human red blood cells (RBCs), where it lives mainly on the abundantly present hemoglobin, multiplies, and releases several daughter cells to repeat the cycle. Consequently, human adaptations to resist malaria involve mutations in surface antigens required for parasite invasion as well as in hemoglobin. One of these hemoglobinopathies is sickle cell disease (SCD), which is caused by a single point mutation in the beta subunit. In homozygous carriers, low oxygen tension in the micro vascularity causes polymerization of hemoglobin and characteristic sickling of RBCs. SCD is lethal if left untreated. Heterozygous carriers (or sickle trait carriers) are mostly asymptomatic but show a 90% reduced risk of developing severe malaria if infected. Due to this protection, rates of SCD can reach almost 20% in affected Sub-Saharan countries. This selective pressure in turn causes adaptations in the parasite itself. A recent study identified mutations in three parasite genes that are strongly associated with disease in sickle cell patients. Presence of all three mutations almost entirely abolished the protective properties of SCD. A spread of these mutant parasites in regions with high SCD rates could endanger large parts of the population previously protected from malaria. The parasite genes were termed Plasmodium falciparum sickle associated (Pfsa). Very little is known about any of those proteins, and there is no clear connection in function. The FUP strain carries, unlike most laboratory strains, all three Pfsa mutations. This allows the comparison of the two genotypes in phenotypic assays. The project involves two distinct aims: Aim 1 studies differences in growth between the two cell lines in different blood types (healthy vs sickle trait vs SCD) and at different oxygen tensions. Finally, wild type Pfsa will be replaced with the mutant alleles to validate their impact on parasite growth. Aim 2 focuses on direct characterization of the Pfsa proteins. Most Pfsa in wild type and mutant background were tagged with a small epitope tag and an inducible knockout system. These cell lines will be used to determine sub-cellular localization, essentiality and protein interaction partners.

Basic Science

Jan 2024 — Dec 2025

$155,824

United States