TRANSGENIC MICE EXPRESSING HUMAN FETAL GLOBIN ARE PROTECTED FROM MALARIA BY A NOVEL MECHANISM

Studies in vitro by Pasvol et al (Nature, 270:171, 1977) have indicate d that the growth of Plasmodium falciparum in cells containing fetal h emoglobin (HbF = alpha(2)gamma(2)) is retarded, but invasion is increa sed, at least in newborn cells. Normal neonates switch from about 80% HbF at birth to a few percent at the end of the first year of life. Ca rriers of P-thalassemia trait exhibit a delay in the normal HbF switch -off, which might partially explain the protection observed in populat ions with this gene. To study this hypothesis in vivo, we used transge nic (gamma) mice expressing human Ar and Gr chains resulting in 40% to 60% alpha(2)(M)gamma(2) hemoglobin, infected with rodent malaria. Two species of rodent malaria were studied. P chabaudi adami causes a non lethal infection, mainly in mature red blood cells (RBC). P yoelii 17X NL is a nonlethal infection, invading primarily reticulocytes, whereas P yoelii 17XL is a lethal variant of P yoelii 17XNL and causes death of mice in approximately 1 to 2 weeks. Data indicate that this strain may cause a syndrome resembling cerebral malaria caused by P falciparu m (Am J Trop Med Hyg, 50:512, 1994). In gamma transgenic mice infected with P chabaudi adami, the parasitemia rose more quickly (in agreemen t with Pasvol) than in control mice, but was cleared more rapidly. In mice infected with P yoelii 17XNL, a clear reduction in parasitemia wa s observed. Interestingly, splenectomy before this infection, did not reverse protection. The most striking effect was in lethal P yoelii 17 XL infection. Control mice died between 11 to 13 days, whereas gamma m ice cleared the infection by day 22 and survived, a phenomenon also ob served in splenectomized animals. These results suggest that HbF does indeed have a protective effect in vivo, which is not mediated by the spleen. In terms of mechanisms, light microscopy showed that intraeryt hrocytic parasites develop slowly in HbF erythrocytes, and electron mi croscopy showed that hemozoin formation was defective in transgenic mi ce. Finally, digestion studies of HbF by recombinant plasmepsin II dem onstrated that HbF is digested only half as well as hemoglobin A (HbA) . We conclude that HbF provides protection from P falciparum malaria b y the retardation of parasite growth. The mechanism involves resistanc e to digestion by malarial hemoglobinases based on the data presented and with the well-known properties of HbF as a super stable tetramer. In addition, the resistance of normal neonates for malaria can now be explained by a double mechanism: increased malaria invasion rates, rep orted in neonatal RBC, will direct parasites to fetal cells, as well a s F cells, and less to the approximate to 20% of HbA containing RBC, a mplifying the antimalarial effects of HbF. (C) 1998 by The American So ciety of Hematology.