| Popis: |
The clinical outcome of Plasmodium falciparum (P. falciparum) infection depends on a combination of timely treatment, pre-existing immunity and host genetic factors. An increasingly important role is attributed to these host genetic factors which are now believed \ud to play a critical role in disease pathogenesis. The host red blood cell (RBC) serves an essential role in the life cycle of P. falciparum; understanding variations in the molecular and cell biology of this cell type leads to essential insights into the variations observed in disease outcomes. The aim of this thesis is to study functional RBC variants, characteristics and mechanisms by which protection against malaria may be mediated. I investigated three distinct characteristics of host RBCs for their effect on malaria pathogenesis and drug susceptibility.\ud \ud First, I investigated the impact of host iron deficiency on the susceptibility of P. falciparum to the front-line antimalarial drug, artemisinin. Since previous work has shown that artemisinin is activated by heme iron and that the efficacy of artemisinin against malaria parasites is directly linked to the amount of free heme in the host RBCs, we reasoned that host haemoglobin levels may alter the susceptibility of P. falciparum to artemisinin. Fortunately for public health programs in Sub Saharan Africa, low iron status in the host did not impact artemisinin activity or the susceptibility of artemisinin-resistant parasites. \ud \ud Second, I investigated the association of the Q248H polymorphism in the ferroportin gene with malaria pathogenesis. Ferroportin is an iron exporter found in RBCs. The Q248H polymorphism has been previously reported to decrease the degradation of ferroportin by hepcidin and to be associated with protection from malaria. To further investigate this, I investigated ex vivo P.falciparum growth in RBCs from pregnant women and children in rural Gambia with this polymorphism. I observed no excess malaria growth in Q248H RBCs ex vivo. This indicates that the Q248H mutation does not deprive malaria parasites entirely of iron. \ud \ud Third, I investigated the role of polymorphisms in the human gene ATP2B4 on the erythrocytic lifecycle of P. falciparum. ATP2B4 codes for PMCA4b, the major plasma membrane calcium pump in RBCs. Recent genome wide association and cross-sectional studies have identified novel polymorphisms associated with decreased malaria risk in ATP2B4. I focused on a variant haplotype in ATP2B4 composed of 17 single nucleotide polymorphisms (SNPs) that are in strong linkage disequilibrium. I found a reduced rate of PMCA4b expression, calcium expulsion and P. falciparum growth in RBCs from participants homozygous for the mutant haplotype. I concluded that this variant ATP2B4 haplotype, which has a high minor allele frequency in West African populations, protects against severe malaria by controlling parasite density. |
