Magneto-chemical speciation of pathogenic iron deposits in thalassaemia and malaria

Seval Hackett

    Research output: ThesisDoctoral Thesis

    183 Downloads (Pure)

    Abstract

    [Truncated abstract] Iron is essential to most biological systems. Under pathological conditions affecting the iron metabolic pathway, iron can be deposited in the tissue in various forms. The work presented in this thesis has exploited the relationship between the magnetic and the chemical properties of tissue iron deposits to further understanding of two major pathologies, the haemoglobinopathies termed thalassaemias and the malaria parasite Plasmodium falciparum, both amongst the most common health concerns in tropical countries. The iron-specific magnetic susceptibilities χFe for spleen tissue samples from 7 transfusion dependent β-thalassaemia (β-thal) patients and 11 non-transfusion dependent β-thalassaemia/Haemoglobin E (β/E) patients were measured at 37°C. Both groups of patients were iron loaded with no significant difference in the distribution of spleen iron concentrations between the two groups. There was a significant difference between the mean χFe of the spleen tissue from each group. The β/E patients had a higher mean (± standard deviation) spleen χFe (1.55 ± 0.23 × 10-6 m3.kgFe -1) than the β-thal patients (1.16 ± 0.25 × 10-6 m3.kgFe -1). Correlations were observed between χFe of the spleen tissue and the fraction of magnetic hyperfine split sextet in the 57Fe Mössbauer spectra of the tissues at 78 K (Spearman rank order correlation ρ = -0.54, p = 0.03) and between χFe of the spleen tissue and the fraction of doublet in the spectra at 5 K (ρ = 0.58, p = 0.02) indicating that χFe of the spleen tissue is related to the chemical speciation of the iron 2 deposits in the tissue. The biological variability of the iron-specific magnetic susceptibility of the tissue iron examined would contribute a random uncertainty of 19% to magnetic susceptibility based non-invasive measurements of tissue iron concentration. ... Magnetic susceptibility measurements were also performed on malaria parasitised red blood cells. In vitro cultures of P. falciparum were magnetically enriched up to 61-fold using high field gradient magnetic separation columns, and the magnetic susceptibility of cell contents was directly measured. Forms of haem iron were quantified spectroscopically. Further fractionations were performed such that, by controlling the fluid velocity through the column, cells with more than a critical amount of paramagnetic 3 iron were preferentially extracted. A chloroquine-sensitive (CQS) laboratory strain of parasites converted approximately 60% of host cell haem iron to haemozoin and this product was the primary source of the increase in cell magnetic susceptibility. The volumetric magnetic susceptibility of the magnetically enriched cells was found to be 0.15 ± 0.03 × 10-7 relative to the suspension medium, accounting for the enrichment of mature parasites. Comparisons of fractionation samples of two pairs of CQS and chloroquine resistant (CQR) strains showed enrichment of mature parasites was significantly greater in the CQS than the CQR strains. The results suggest the possibility of using magnetic separation columns in identifying CQR strains of P. falciparum, potentially in a diagnostic or research setting. The study also underlines the need to identify and quantify the forms of iron in CQR and CQS parasite strains as the fate of haem iron will have implications in understanding the mechanisms of chloroquine resistance.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Publication statusUnpublished - 2007

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