Transgenic mice expressing human sickle hemoglobin are partially resistant to rodent malaria

Shear, HL; Röth, Elizabeth; Fabry, ME; Costantini, FD; Pachnis, A; Hood, Andrew; Nagel, RL

doi:10.1182/blood.v81.1.222.bloodjournal811222

Cited by 18 publications

(23 citation statements)

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“…Examples include the apparent change in HEMP1 accessibility to antibody in thalassaemic red blood cells, which appears to make parasites more susceptible to clearance by immune mechanisms (Luzzi et al, 1991a,b). Transgenic mice with specific abnormalities of red blood cells have been examined for susceptibility to malaria infection (Shear, 1993;Shear et al, 1993Shear et al, , 1998Hood et al, 1996). In general, these studies have confirmed the importance of abnormal haemoglobin in restricting parasite growth.…”

Section: The Host-parasite Relationshipmentioning

confidence: 91%

The malaria-infected red blood cell: Structural and functional changes

Cooke

Mohandas

Coppel

2001

Advances in Parasitology

187

149

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The asexual stage of malaria parasites of the genus Plasmodium invade red blood cells of various species including humans. After parasite invasion, red blood cells progressively acquire a new set of properties and are converted into more typical, although still simpler, eukaryotic cells by the appearance of new structures in the red blood cell cytoplasm, and new proteins at the red blood cell membrane skeleton. The red blood cell undergoes striking morphological alterations and its rheological properties are considerably altered, manifesting as red blood cells with increased membrane rigidity, reduced deformability and increased adhesiveness for a number of other cells including the vascular endothelium. Elucidation of the structural changes in the red blood cell induced by parasite invasion and maturation and an understanding of the accompanying functional alterations have the ability to considerably extend our knowledge of structure-function relationships in the normal red blood cell. Furthermore, interference with these interactions may lead to previously unsuspected means of reducing parasite virulence and may lead to the development of novel antimalarial therapeutics.

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Section: The Host-parasite Relationshipmentioning

confidence: 91%

The malaria-infected red blood cell: Structural and functional changes

Cooke

Mohandas

Coppel

2001

Advances in Parasitology

187

149

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“…In particular, this approach enables the study of the role of the reticuloendothelial system in the recognition of infected erythrocytes under well-controlled experimental conditions. Important results have been already achieved by Shear et al (1993Shear et al ( , 1994, who observed that in transgenic p*S mice splenectomy reverses completely the protection against l? chabaudi adami infection.…”

Section: Current Understanding Ofmentioning

confidence: 97%

“…Also in the case of HbS, accelerated phagocytosis of infected erythrocytes would provide the most efficient level of protection. It has been in fact observed that splenectomy of P*S transgenic mice completely reverses the protection against Plasmodium chabaudi adami infection (Shear 1993;Shear et al, 1994). Furthermore, HbSS subjects, who have anatomical and functional asplenia, have no or reduced resistance against the infection (Luzzatto and Pinching, 1990).…”

Section: Protection Afforded By Dietary Intakes Of Oxidative Substancesmentioning

confidence: 99%

Interaction between oxidized hemoglobin and the cell membrane: A common basis for several falciparum malaria‐linked genetic traits

Destro‐Bisol¹,

Giardina²,

Sansonetti³

et al. 1996

Am. J. Phys. Anthropol.

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KEY WORDSlinked genetic traits, Membrane bound hemoglobin Oxidative stress, falciparum malaria, Malaria- ABSTRACTThis paper focuses on the interaction between oxidized hemoglobin and the erythrocyte membrane, and its relevance to some falciparum malaria-linked genetic traits. We first present the experimental evidence which suggests that the interaction between hemoglobin derivatives and membrane proteins is an important cellular mechanism for the erythrocytes carrying HbS, HbE, HbF, a-and P-thalassemia, and GGPD deficiency. Thereafter, we show how the Hblmembrane interaction might act as primum movens for diverse cellular mechanisms which 1) reduce invasion of erythrocytes by the falciparum parasite; 2) impair parasite survival and development within the cell; 3) accelerate infected erythrocyte clearance by phagocytosis. We claim that oxidative stress is the driving force of this process, since highly reactive species (like 0,-and H202) mediate the gradual oxidation of Hb to irreversible hemichrome-containing Heinz bodies. We therefore suggest that positing the interaction between oxidized hemoglobin and cell membrane as a common basis for several falciparum malaria-linked genetic traits is not only consistent with experimental evidence gathered so far, but provides a new, clearer perspective: the molecular event on which these known protective traits rest. In the last part of the paper we will discuss two case studies which provide further support for the role played by hemoglobin derivatives and membrane proteins: 1) the influence of a cyanogen-rich diet on the distribution of HbPV gene frequencies in Liberia (Jackson [1990] Am.

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“…Choroid abnormalities were later confirmed in human autopsies (Fukushima et al , 1997). This model has been useful in the elucidation of the mechanisms of malaria protection afforded by the β S gene in vivo (Shear et al , 1993), particularly the important role of the spleen in this innate resistance. Osarogiagbon et al (1997) have provided in vivo evidence of oxidative stress in hypoxia‐exposed mice of this lineage.…”

mentioning

confidence: 99%

The panoply of animal models for sickle cell anaemia

Nagel¹,

Fabry²

2001

Br J Haematol

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A transgenic mouse model expressing exclusively haemoglobin S has been an active objective of sickle cell anaemia research in the last decade because it can: (i) help to understand the pathophysiology of the disease; (ii) help in the development of anti-sickling drugs; and (iii) have potential usefulness for dry runs of anti-sickling gene therapy.Three groups have reported sickle transgenic mouse lines that express only human globin chains Ryan et al, 1997;Chang et al, 1998). This accomplishment required the`knockout' of the murine globin genes, that is, the removal or inactivation of these genes by homologous recombination (Ciavetta et al, 1995;Pa Ászty et al, 1995;Yang et al, 1995;Chang et al, 1998). The strategy used to generate the`knockout' models is described in Fig 1. A better perspective on the characteristics of knockout models with exclusively human globin chains is obtained by first discussing the sickle transgenic models previously available (which are still useful for defined purposes) and contrasting them with the new models.Models with a combination of murine globins and human globin chains The first models expressing moderately high levels of both human a-and b S -globin chains were reported by Greaves et al (1990) and Ryan et al (1990). The former was not propagated and the latter expressed only about 50% b S . Subsequently, many different lines of mice with variable degrees of severity became available allowing more detailed studies of pathology.The SAD-1-mouse. This mouse, generated/characterized by Trudel et al (19911994), expresses the SAD transgene at 19% that contains three mutations (b S , b S±Antilles and b DLos Angeles or b SAD ) in the same b chain (Trudel et al, 1991). The last two mutations enhance polymer formation. When the b major deletion (Skow et al, 1983) is present as the hemizygote (b-thal/SAD or SAD-1/b d3 ), the percentage of b SAD increases to 26% and the phenotype is severe. A human a-globin gene is co-integrated at the same site. This model has been used to test clotrimazol, a Gardos channel blocker that inhibits dense-cell formation and to test Mg 11 supplementation (De Franceschi et al, 1994. The model has provided information on glomerular abnormalities and could be useful for testing therapeutic approaches for priapism. Recently, ineffective erythropoiesis has been demonstrated in SAD and SAD-1/ b d3 mice (Blouin et al, 1999).Blouin et al (2000) have recently described the effect of introducing several levels of human g on the SAD-1 mouse that has no deletions or knockouts. The effect of g on transgenic mouse models is important for both understanding the mechanism of the protective effect of g and as a baseline for evaluating anti-sickling haemoglobins proposed for use in gene therapy. Four different levels of human g were bred into the SAD-1 mouse resulting in mice expressing 5´2, 10´6, 18´4 and 24´4% g as a percentage of all b-like chains; there was a concomitant decrease in the percentage of SAD haemoglobin that was not quantified. The effect of the SAD transgene...

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Transgenic mice expressing human sickle hemoglobin are partially resistant to rodent malaria

Cited by 18 publications

References 0 publications

The malaria-infected red blood cell: Structural and functional changes

The malaria-infected red blood cell: Structural and functional changes

Interaction between oxidized hemoglobin and the cell membrane: A common basis for several falciparum malaria‐linked genetic traits

The panoply of animal models for sickle cell anaemia

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