CATCHING MALARIA INFECTED RED BLOOD CELLS: A BIOPHYSICAL STUDY OF ICAM-1 MEDIATED CYTOADHESION USING IN VITRO METHODS

Abstract

Plasmodium (P.) falciparum malaria infected red blood cells (IRBCs) avoid splenic clearance by adhering to host endothelium. Upregulation of endothelial ICAM-1 and CD36 have been associated with severe disease pathology, but only ICAM-1 is highly expressed in the brain. This thesis aims to understand IRBC-ICAM-1 interactions from a biophysical perspective, using IRBC-CD36 bonds as a comparison. Single bond force spectroscopy was first conducted to study the nature of IRBC-ICAM-1 bonds and obtain bond dissociation parameters. Fever experienced during malaria infection subsequently motivated us to investigate the impact of temperature - 37°C (body) and 41°C (febrile) - on IRBC-ICAM-1 dissociation. Thereafter, we studied IRBC-ICAM-1 association. A cellular stochastic model was developed to indirectly extract bond association parameters from a flow assay using dissociation rates obtained earlier. Likewise, experiments were performed at 25°C, 37°C and 41°C. Results presented in this dissertation provide insight to IRBC-ICAM-1 adhesion kinetics and adjunctive treatment for malaria.