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Protection against severe malaria by haemoglobinopathic erythrocytes

Srismith, Sirikamol

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Abstract

Although the molecular mechanisms by which haemoglobinopathic erythrocytes protect their carriers against life-threatening complications of severe malaria have yet to be elucidated, one of the contributing factors is believed to be reduced cytoadhesion in the microvasculatures of vital organs. Previous studies have described perturbations in host actin remodelling, reduced surface levels of PfEMP1 adhesin, abnormal knob sizes and distributions as well as malformed Maurer’s clefts in infected haemoglobinopathic erythrocytes, relative to those seen in infected HbAA erythrocytes. We attempted to establish super-resolution imaging with direct stochastic optical reconstruction microscopy (dSTORM) as an intermediate throughput method of visualising host actin remodelling in infected erythrocytes. Unfortunately, individual F-actin and spectrin filaments could not be resolved and no significant differences in the actin and spectrin labelling of uninfected versus infected erythrocytes were distinguishable. We also further explored the kinetics of adhesion phenotype and protein transport in haemaglobinopathic erythrocytes. We found that infected HbAS erythrocytes exhibited slower temporal increase in number of adherent cells as well as a lower total number of adherent cell relative to infected HbAA erythrocytes. A delay in the establishment of new permeability pathway (NPP) was also observed in infected haemoglobinopathic erythrocytes. We tested the hypothesis that the inherent redox imbalance found in uninfected haemoglobinopathic erythrocytes is the beginning of a cascade of events which precipitates in the reduced cytoadhesive phonotype associated with protection against severe malaria. By exposing uninfected HbAA erythrocytes to transient oxidative stress, we were able to mimic various phenotypes associated with the protective traits, including reduced cytoadhesion and surface PfEMP1 levels, malformed and dispersed knobs, aberrant Maurer’s cleft morphologies and inability to remodel host actin cytoskeleton. Taken together, our findings describe a cascade of events which begins with the redox imbalance inherent to uninfected haemoglobinopathic erythrocytes. This oxidative milieu interferes with parasitic protein export, host actin remodelling and knobs and Maurer’s cleft formation, which leads to aberrant display of PfEMP1 on the cell surface and a reduced level of cytoadhesion. This helps to alleviate the life-threatening consequences of severe malaria.

Item Type: Dissertation
Supervisor: Lanzer, Prof. Dr. Michael
Date of thesis defense: 10 September 2018
Date Deposited: 15 Nov 2018 08:19
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences

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  • Protection against severe malaria by haemoglobinopathic erythrocytes. (deposited 15 Nov 2018 08:19) [Currently Displayed]
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