Investigations of anti-adhesion and endothelial environment for plasmodium falciparum cytoadherence

Mustaffa, Khairul Investigations of anti-adhesion and endothelial environment for plasmodium falciparum cytoadherence. Doctor of Philosophy thesis, University of Liverpool.

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Abstract

A unique feature of mature Plasmodium falciparum (P. falciparum) parasitized RBC (pRBC) is that they bind to surface molecules of microvasculature endothelium via the parasite-derived surface protein PfEMP1. This ligand is associated with the cytoadherence pathology seen in severe malaria (SM) and recently our group has shown that even when treated with effective anti-malarial drug, pRBC are still able to cytoadhere, therefore, there is a need to find an adjunct treatment (in addition to antimalarial drugs) that can inhibit and reverse the adhesion process. Previous reports have suggested that sulphated glycoconjugates are highly effective at disrupting P. falciparum pRBC rosettes. Here, we investigate that effect by using sulphated polysaccharides and modified heparin for their effect to interrupt pRBC sequestration. We found that not all sulphated compounds or modified heparins were able to interrupt the sequestration process. Consideration of the inhibitory compounds generated some 18rules 19 fore exhibition of inhibitory properties: Sulphate position either at 6-O, or/and 2-O sulphate and N-sulphate is necessary for each compound. In addition, the multivalent effect and drug exhibit low anticoagulant activity also determined an active response to inhibit and de-sequestered P. falciparum pRBC on protein and endothelial cells. Here, we provide evidence that polysaccharides that possess a different level of sulphate, conformational structure and sulphate position act differently. This study also addressed the importance of pH host environment and extracellular matrix (glycocalyx) on the surface of endothelial cells on mediating pRBC binding. It found that pRBC bind significantly higher at pH 7-7.2 to CD36 and ICAM-1. Meanwhile, glycocalyx might interact as an instantaneous binder before pRBC reached ICAM-1 or CD36, unfortunately we cannot prove this due to methods and antibody chosen. The work reported in this thesis opens up new possibilities for therapeutic strategies targeting binding interaction of pRBC to host cells.

Item Type:	Thesis (Doctor of Philosophy)
Additional Information:	Date: 2011-12 (completed)
Uncontrolled Keywords:	Malaria cytoadherence, Glycoaminoglycan
Divisions:	Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	07 Aug 2012 10:46
Last Modified:	16 Dec 2022 04:36
DOI:	10.17638/00005773
Supervisors:	Craig, Alister
URI:	https://livrepository.liverpool.ac.uk/id/eprint/5773