Chloroquine resistant malaria: Association with enhanced plasmodial protease activity

Chloroquine resistant Plasmodium berghei has several unusual features including (i) lack of malaria “pigment”, (ii) more efficient host catabolism of heme from infected erythrocytes, and (iii) relatively inefficient uptake of external chloroquine by infected red cells. The malaria pigment produced by chloroquine sensitive P. berghei is probably incompletely catabolized hemoglobin, the heme group of which is unavailable for subsequent catabolism by the host's reticuloendothelial system. This pigment has been suggested by others as the site of high affinity chloroquine binding. We hypothesized that all three characteristics of chloroquine resistant infections might be explained by enhanced proteolytic digestion of host cell hemoglobin. In confirmation, we report that chloroquine resistant P. berghei has 700–800% greater protease activity than the chloroquine sensitive form. This greatly elevated protease activity may explain the aforementioned characteristics of chloroquine resistant P. berghei and may help elucidate the basis of chloroquine resistance in human P. falciparum.