title: Transgenic mice expressing human fetal globin are protected from malaria by a novel mechanism.
abstract: Studies in vitro by Pasvol et al (Nature, 270:171, 1977) have indicated that the growth of Plasmodium falciparum in cells containing fetal hemoglobin (HbF = alpha2gamma2) is retarded, but invasion is increased, 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. Carriers of beta-thalassemia trait exhibit a delay in the normal HbF switch-off, which might partially explain the protection observed in populations with this gene. To study this hypothesis in vivo, we used transgenic (gamma) mice expressing human Agamma and Ggamma chains resulting in 40% to 60% alpha2Mgamma2 hemoglobin, infected with rodent malaria. Two species of rodent malaria were studied. P chabaudi adami causes a nonlethal infection, mainly in mature red blood cells (RBC). P yoelii 17XNL 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 falciparum (Am J Trop Med Hyg, 50:512, 1994). In gamma transgenic mice infected with P chabaudi adami, the parasitemia rose more quickly (in agreement with Pasvol) than in control mice, but was cleared more rapidly. In mice infected with P yoelii 17XNL, a clear reduction in parasitemia was observed. Interestingly, splenectomy before this infection, did not reverse protection. The most striking effect was in lethal P yoelii 17XL infection. Control mice died between 11 to 13 days, whereas gamma mice cleared the infection by day 22 and survived, a phenomenon also observed 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 intraerythrocytic parasites develop slowly in HbF erythrocytes, and electron microscopy showed that hemozoin formation was defective in transgenic mice. Finally, digestion studies of HbF by recombinant plasmepsin II demonstrated that HbF is digested only half as well as hemoglobin A (HbA). We conclude that HbF provides protection from P falciparum malaria by the retardation of parasite growth. The mechanism involves resistance 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, reported in neonatal RBC, will direct parasites to fetal cells, as well as F cells, and less to the approximately 20% of HbA containing RBC, amplifying the antimalarial effects of HbF.
authors.affiliation: Division of Hematology, Department of Medicine, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY 10467, USA.
authors.forename: H L
authors.initials: HL
authors.lastname: Shear
authors.forename: L
authors.initials: L
authors.lastname: Grinberg
authors.forename: J
authors.initials: J
authors.lastname: Gilman
authors.forename: M E
authors.initials: ME
authors.lastname: Fabry
authors.forename: G
authors.initials: G
authors.lastname: Stamatoyannopoulos
authors.forename: D E
authors.initials: DE
authors.lastname: Goldberg
authors.forename: R L
authors.initials: RL
authors.lastname: Nagel
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004198:Disease Susceptibility; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D005319:Fetal Hemoglobin / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005914:Globins / Q000096:biosynthesis / Q000235:genetics; D006790:Host-Parasite Interactions; D008288:Malaria / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018512:Parasitemia / Q000097:blood / Q000517:prevention & control; D016788:Plasmodium chabaudi / Q000472:pathogenicity*; D010963:Plasmodium falciparum / Q000201:enzymology; D010967:Plasmodium yoelii / Q000472:pathogenicity*; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D015800:Protozoan Proteins; D011994:Recombinant Proteins; D005914:Globins; D005319:Fetal Hemoglobin; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II