City Research Online

Abstract

Despite major reductions in clinical cases and mortality over the last half century, malaria remains a major public health threat with an estimated 241 million cases and 627 000 deaths in 2021. Our arsenal of effective treatment options continues to be threatened by the emergence of drug resistance, thus highlighting a need for new drugs and drug combinations with novel modes of action. Transition metals such as iron, copper and zinc are essential to the survival of the malaria parasite Plasmodium falciparum, but become toxic at high concentrations. Hence, the careful regulation of transition metals is required as the parasite progresses through its complex life cycle. With that considered, the perturbation of transition metal homeostasis is an attractive approach for novel malaria control strategies. The work presented herein aimed to characterise several putative transition metal transporters from P. falciparum, to better understand their role in transition metal homeostasis. The sole cation diffusion facilitator expressed by P. falciparum (PfCDF) was shown to confer zinc tolerance to a zinc-sensitive yeast line, but not tolerance to cobalt or iron. Using similar yeast systems, it was shown that putative copper transporters PfCTR1 and PfCTR2 did not rescue the growth phenotype of a copper-sensitive yeast line, nor did the chloroquine resistance transporter, PfCRT, confer tolerance to iron in an iron-sensitive yeast line. Furthermore, reverse genetics approaches were undertaken which aimed to generate parasite lines that featured mutated putative transporter genes, to enable the study of protein essentiality, substrate specificity and sub-cellular localisation. Finally, the effects of iron on artemisinin (current frontline antimalarial drug) action were also explored. Whilst malarial proteins involved in transition metal homeostasis remain reasonably understudied, the work presented in this thesis builds on existing foundations of a promising area of investigation and leaves a clear trajectory for further exploration.

Publication Type:	Thesis (Doctoral)
Subjects:	Q Science > QR Microbiology Q Science > QR Microbiology > QR180 Immunology R Medicine
Departments:	School of Health & Medical Sciences > Infection and Immunity Research Institute School of Health & Medical Sciences > School of Health & Medical Sciences Doctoral Theses Doctoral Theses

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