Transgenic Mice Expressing Human Fetal Globin Are Protected From Malaria by a Novel Mechanism

摘要: Studies in vitro by Pasvol et al (Nature, 270:171, 1977) have indicated that the growth of Plasmodium falciparum cells containing fetal hemoglobin (HbF = alpha2gamma2) is retarded, but invasion increased, at least newborn cells. Normal neonates switch from about 80% HbF birth to a few percent end first year life. Carriers beta-thalassemia trait exhibit delay normal switch-off, which might partially explain protection observed populations with this gene. To study hypothesis vivo, we used transgenic (gamma) mice expressing human Agamma and Ggamma chains resulting 40% 60% alpha2Mgamma2 hemoglobin, infected rodent malaria. Two species malaria were studied. P chabaudi adami causes nonlethal infection, mainly mature red blood (RBC). yoelii 17XNL invading primarily reticulocytes, whereas 17XL lethal variant death approximately 1 2 weeks. Data indicate strain may cause syndrome resembling cerebral caused (Am J Trop Med Hyg, 50:512, 1994). In gamma adami, parasitemia rose more quickly (in agreement Pasvol) than control mice, was cleared rapidly. 17XNL, clear reduction observed. Interestingly, splenectomy before did not reverse protection. The most striking effect infection. Control died between 11 13 days, infection day 22 survived, phenomenon also splenectomized animals. These results suggest does indeed protective mediated spleen. terms mechanisms, light microscopy showed intraerythrocytic parasites develop slowly erythrocytes, electron hemozoin formation defective mice. Finally, digestion studies recombinant plasmepsin II demonstrated digested only half as well A (HbA). We conclude provides retardation parasite growth. mechanism involves resistance malarial hemoglobinases based on data presented well-known properties super stable tetramer. addition, for can now be explained double mechanism: increased rates, reported neonatal RBC, will direct cells, F less 20% HbA amplifying antimalarial effects HbF.