Adhesion analysis of different PfEMP1 variants to CD36, ICAM-1 and primary endothelial cells



Madkhali, Aymen
Adhesion analysis of different PfEMP1 variants to CD36, ICAM-1 and primary endothelial cells. PhD thesis, University of Liverpool.

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Abstract

Malaria is an ancient vector-borne disease that still has a huge impact on global health. Malaria pathogenesis is developed during the asexual intraerythrocytic stage where P. falciparum modifies the host erythrocytes by exporting repertoires of parasite proteins on to the surface of infected erythrocytes. PfEMP1 is one of these proteins that mediate different functions including the adhesion of IEs to the host receptors such as CD36, ICAM-1 and EPCR. The current study has characterised the adhesion of infected erythrocytes with different PfEMP1 variants to CD36, ICAM-1 and primary endothelial cells. The characterisation was carried using static protein and flow endothelial adhesion assays. First, the characterisation involved an analysis of the binding of recently selected ICAM-1 binding P. falciparum patient isolates on different ICAM-1 variants. The results showed that different isolates have variant-specific binding phenotypes suggesting that there might be variable contact residues on ICAM-1 being used by different parasite PfEMP1 variants. This observation was more emphasised by the adhesion of isogenic isolates that has been confirmed to express ICAM-1 binding domain from IT4 parasites. The second part of the study has characterised the adhesion of IEs with upsC PfEMP1 isolates from HB3 and IT4 isolates on CD36, ICAM-1 and endothelial cells. Three upsC IT4 isolates bound to CD36 and one of these isolates bound to ICAM-1 because it expresses DBLβ-ICAM-1 binding domain. In contrast, HB3 upsC isolates did not show preferential binding to CD36, ICAM-1 and the endothelial cells despite showing cross reactivity with adult hyperimmune sera. Finally, the adhesion of IEs with different length PfEMP1s was analysed. It was concluded that long PfEMP1 adapted to bind efficiently the short, but this might be due to the lack of variety of DBLs for adhesion in the short forms. Therefore, it is suggested that it is the domain constitution rather than size that seems to be important.

Item Type: Thesis (PhD)
Additional Information: Date: 2015-01 (completed)
Depositing User: Symplectic Admin
Date Deposited: 11 Aug 2015 09:41
Last Modified: 17 Dec 2022 01:33
DOI: 10.17638/02010340
URI: https://livrepository.liverpool.ac.uk/id/eprint/2010340