|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2520-2526
Transgenic Mice Expressing Human Fetal Globin Are Protected From
Malaria by a Novel Mechanism
Hannah L. Shear,
Leonid Grinberg,
John Gilman,
Mary E. Fabry,
George Stamatoyannopoulos,
Daniel E. Goldberg, and
Ronald L. Nagel
From the Division of Hematology, Department of Medicine, Montefiore
Medical Center/Albert Einstein College of Medicine, Bronx, NY; the
Division of Human Genetics, University of Washington, Seattle, WA; and
the Howard Hughes Medical Institute, Department of Medical and
Molecular Microbiology, Washington University, St Louis, MO.
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 =  2 2) 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  -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 () mice expressing human A
and G chains resulting in 40% to 60%
2M2 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 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 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  20% of HbA containing RBC, amplifying
the antimalarial effects of HbF.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
A. A. DJIMDE, O. K. DOUMBO, O. TRAORE, A. B. GUINDO, K. KAYENTAO, Y. DIOURTE, S. NIARE-DOUMBO, D. COULIBALY, A. K. KONE, Y. CISSOKO, et al.
CLEARANCE OF DRUG-RESISTANT PARASITES AS A MODEL FOR PROTECTIVE IMMUNITY IN PLASMODIUM FALCIPARUM MALARIA
Am J Trop Med Hyg,
November 1, 2003;
69(5):
558 - 563.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Fairhurst, H. Fujioka, K. Hayton, K. F. Collins, and T. E. Wellems
Aberrant development of Plasmodium falciparum in hemoglobin CC red cells: implications for the malaria protective effect of the homozygous state
Blood,
April 15, 2003;
101(8):
3309 - 3315.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. I. Brinkworth, P. Prociv, A. Loukas, and P. J. Brindley
Hemoglobin-degrading, Aspartic Proteases of Blood-feeding Parasites. SUBSTRATE SPECIFICITY REVEALED BY HOMOLOGY MODELS
J. Biol. Chem.,
October 12, 2001;
276(42):
38844 - 38851.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. E. Fabry, S. M. Suzuka, R. S. Weinberg, C. Lawrence, S. M. Factor, J. G. Gilman, F. Costantini, and R. L. Nagel
Second generation knockout sickle mice: the effect of HbF
Blood,
January 15, 2001;
97(2):
410 - 418.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
