THALASSEMIA TRAIT, RED-BLOOD-CELL AGE AND OXIDANT STRESS - EFFECTS ONPLASMODIUM-FALCIPARUM GROWTH AND SENSITIVITY TO ARTEMISININ

Knowledge of innate mechanisms of protection against malaria could be used to bolster the existing limited treatments. Oxidant stress may pl ay a role in the protective mechanism and the effect of red blood cell (RBC) age has recently been recognized. This study investigated the r ole of oxidant stress in the protection against malaria in thalassaemi c trait RBC (alpha and beta) using an experimental approach which cont rolled for cell age. 'Young', 'intermediate' and 'old' RBC obtained by Percoll(R) fractionation and whole blood were used to set up malaria cultures. Antioxidants (vitamin E and dithiothreitol) and prooxidants (riboflavin, menadione and artemisinin) were added to modulate oxidant stress effect. Antioxidants improved parasite growth. The degree of i mprovement was significantly greater with increasing RBC age (P<0.0001 ), and relatively greater in thalassaemic RBC (P<0.0001). Pro-oxidants had a parasiticidal effect. With the exception of the 'old' RBC fract ion, the median inhibitory concentration (IC50) for riboflavin and men adione was significantly higher in normal RBC. In contrast, the IC50 f or artemisinin was significantly higher in 'old' thalassaemic RBC but was similar in the 'young' and 'intermediate' fractions and whole bloo d. These findings suggest that oxidant stress plays a role in mediatin g the protection against malaria in thalassaemic RBC. Vitamin E and ot her antioxidant supplementation could feasibly exacerbate clinical mal aria. Conversely, pro-oxidant agents could act as useful adjuvants to therapy. It is important to confirm the reduced sensitivity to artemis inin in 'old' thalassaemic trait RBC, as such an effect may promote se lective pressure for the emergence of resistant parasite strains with widespread use of artemisinin.