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Review in translational hematology
Malarial anemia: of mice and men
Abigail A. Lamikanra,1 Douglas Brown,2 Alexandre Potocnik,2 Climent Casals-Pascual,1,3
Jean Langhorne,2 and David J. Roberts1
1Nuffield
Department of Clinical Laboratory Sciences and National Blood Service Oxford Centre, John Radcliffe Hospital, Oxford, United Kingdom; 2National
Institute for Medical Research, The Ridgeway, London, United Kingdom; 3Medical Research Council Laboratory, Atlantic Road, Fajara, Gambia
Severe malaria is manifest by a variety of
clinical syndromes dependent on properties of both the host and the parasite. In
young infants, severe malarial anemia
(SMA) is the most common syndrome of
severe disease and contributes substantially to the considerable mortality and
morbidity from malaria. There is now
growing evidence, from both human and
mouse studies of malaria, to show that
anemia is due not only to increased hemolysis of infected and clearance of uninfected red blood cells (RBCs) but also to
an inability of the infected host to produce an adequate erythroid response. In
this review, we will summarize the recent
clinical and experimental studies of malaria to highlight similarities and differ-
ences in human and mouse pathology
that result in anemia and so inform the
use of mouse models in the study of
severe malarial anemia in humans. (Blood.
2007;110:18-28)
© 2007 by The American Society of Hematology
Malaria in humans
The vast majority of morbidity and mortality from malaria is
caused by infection with Plasmodium falciparum, although P
vivax, P ovale, and P malariae also are responsible for human
infections. The total burden of disease has recently been estimated
to 515 million episodes annually and malaria is responsible for
18% of all childhood deaths in sub-Saharan Africa, equivalent to
800 000 deaths each year.1,2
The study of malarial anemia has somewhat belatedly excited
academic and professional interest. Severe malarial anemia (SMA)
certainly merits concern as a major public health problem because
of the very large numbers of children affected, and it is likely that
these numbers may increase as drug resistance spreads. Concerns
have also been raised by data from recent vaccine studies, which
suggest that monkeys immunized with erythrocytic-stage antigens,
and that have acquired protection from acute infection, may
succumb to severe anemia during a subacute or chronic phase of
infection.3,4 Moreover, there is increasing awareness of the difficulty of satisfactory treatment by blood transfusion outside specialist centers in many endemic areas as a result of the limited
availability of a rapid and safe supply of blood.1,5
SMA is seen most frequently in areas of very high malaria
transmission and most commonly in young children and pregnant
women.6 The prevalence of anemia, defined as a hematocrit (Hct)
level higher than 0.33, in malaria-endemic areas of Africa, varies
between 31% and 91% in children, and between 60% and 80% in
pregnant women.7,8 Given the high degree of morbidity that is
associated with SMA in children, this term will be used to refer to
severe anemia in this group, unless stated otherwise.
It is very difficult to determine the number of cases of severe
anemia attributable to malaria as the WHO definition of SMA (a
hemoglobin [Hb] concentration of ⬍ 50 g/L [5 g/dL], or a Hct
⬍ 0.15, in the presence of a parasitemia ⬎ 10 000 parasites per
microliter [␮L], and a normocytic blood film) may exclude the
considerable proportion of children admitted with severe anemia
that has a blood smear negative for malaria parasites but that
responds to antimalarial treatment.9,10 It may be difficult to attribute
anemia to a single cause since the background to malarial anemia is
often complex in endemic areas and hematinic deficiencies, genetic
traits, and intercurrent infection all may contribute to anemia (see
Roberts et al11 for review). Nevertheless, a randomized placebocontrolled trial of malaria chemoprophylaxis and iron supplementation in infants, from an endemic area, has shown that malaria
infection was the main etiologic factor underlying anemia.9,12
The pathology of malaria is associated with the blood stage of
infection (for overview of life cycle see Figure 1).13 P falciparum
infections have high multiplication rates while also expressing
clonally variant antigens at the surface of infected erythrocytes
(Pf-EMP-1). Pf-EMP-1 binds to ligands on the surface of endothelial cells and mediates sequestration of infected erythrocytes in
postcapillary venules. Both of these characteristics allow the
P falciparum parasite to evade the host immune system, which
results in the occurrence of high parasitemias with repeated
infections that contribute to the chronic nature of this disease.14
In P vivax and P ovale malaria, high parasitemias are rare as
invasion of erythrocytes is limited to reticulocytes. However,
P vivax can, on occasion, cause severe disease including anemia
with severe hemolysis.15-17
The spectrum of the clinical presentation and severity of
P falciparum infection is broad. In endemic areas, many infections
in semi-immune and immune children and adults present as
uncomplicated febrile illness. In more severe disease, nonimmune
individuals may exhibit a number of syndrome(s) including
anemia, coma, respiratory distress, and hypoglycemia, and have a
high frequency of concurrent bacteremia.18-20 Many children
present with mild, moderate, and even severe anemia without other
syndromes of severe disease. However, severe anemia may be
accompanied by other syndromes of severe disease.18 For example,
children with anemia may also present with malaise, fatigue,
Submitted September 12, 2006; accepted February 20, 2007. Prepublished
online as Blood First Edition paper, March 6, 2007; DOI 10.1182/blood-200609-018069.
© 2007 by The American Society of Hematology
18
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BLOOD, 1 JULY 2007 䡠 VOLUME 110, NUMBER 1
MALARIAL ANEMIA IN MICE AND HUMANS
19
may be a background of normal or low Hb. As such, any
understanding of the pathophysiological processes has ultimately
to be linked to the diverse clinical contexts.
Malaria in mice
Figure 1. Plasmodia life cycle. (A) The asexual life cycle begins when sporozoites
from a female mosquito taking a blood meal enter the circulation and invade
hepatocytes. (B) Up to 10 000 merozoites are formed. Following rupture of the
hepatocyte, infective merozoites are released and invade erythrocytes (RBCs).
(C) Within RBCs, the parasite develops through the stages of rings, trophozoites, and
schizonts. Mature schizonts burst to release erythrocytic merozoites that invade new
RBCs. (D) A small proportion of merozoites in RBCs transform into male and female
gametocytes that are ingested by the mosquito. (E) The male and female gametes
fuse and transform into an öocyst that divides asexually into many sporozoites that
migrate to the salivary glands from where they are released during the next blood
meal. Reproduced from Ocana-Morgher et al13 with permission.
In searching for tractable model systems, we are fortunate that
laboratory mice and rats can be infected with natural species of
rodent malaria. Strictly speaking the rodent host-parasite systems
are not “models” (“representation on a smaller scale” or “an
example”) since the progression of disease may be quite different
than that seen in P falciparum malaria. A detailed comparative
description of the features of the rodent “models” of malaria is
therefore a prerequisite to improving the use of these systems in
understanding severe anemia in human disease.
The scope of mouse models of malaria is enhanced by the
availability of differentially susceptible inbred mouse strains in
which infections can be lethal or nonlethal. The course of infection
and immunologic response of infection is variable but specific for
each host-parasite combination, and always results in anemia
(Table 1; and see Lamb et al31 for review). There are several strains
of Plasmodia that cause infection in mice, such as P chabaudi,
P yoelii, P berghei, and P vinckei. As for P falciparum infections,
P chabaudi invades RBCs of all ages,32-34 while P yoelii has a
preference for reticulocytes35 and therefore may serve better as a
model for P vivax. However, the majority of these parasite-mouse
models demonstrate an acute malaria infection with parasitemias
often exceeding 20%, which is in contrast to severe anemia in
humans where acute malaria frequently occurs with a lower
parasitemia (Table 2).
Pathophysiology of malarial anemia
dyspnoea, or respiratory distress as metabolic acidosis supervenes18,21,22 (for review see English et al23). The age distribution of
the syndromes of severe disease is striking, but poorly understood.
Children born in endemic areas are largely protected from severe
malaria in the first 6 months of life by the passive transfer of
maternal immunoglobulins and by fetal hemoglobin. The presentation of disease changes from severe anemia in children aged
between 1 and 3 years in areas of high transmission to cerebral
malaria in older children in areas of lower transmission.24 As
transmission intensity declines, severe malaria is most frequently
found in older age groups.
The anemia of P falciparum malaria is typically normocytic and
normochromic, with a notable absence of reticulocytes, although
microcytosis and hypochromia may be present due to the very high
frequency of alpha and beta thalassemia traits and/or iron deficiency in many endemic areas25,26 (for a general review of the
hematologic features of malaria infection see Abdalla et al27 and
Roberts et al28). The exact differences in the pathophysiology of
anemia in the various clinical settings, ages, and geographic areas
are poorly defined and surely represent a fruitful field for further
study. A less common form of anemia in malaria is “blackwater
fever” characterized by the sudden appearance of hemoglobin in
the urine associated with irregular use of quinine.29,30
The clinical setting of severe anemia is therefore varied and
complex: acute infection may lead to anemia and/or cerebral
malaria, respiratory distress, and hypoglycemia; and chronic,
repeated infection may lead to severe anemia. In addition, there
In attempting to develop an in vivo model of SMA, it may not be
necessary to demonstrate all features of severe falciparum anemia
but to represent a component of this syndrome that may help to
identify factors that contribute to its severity. These should then be
considered in the context of concurrent infections that may
exacerbate the anemia.36 The examples of possible causes of SMA
given in this article will be from clinical studies in which
participants with coinfections, hemoglobinopathies, or folate or
G6PD deficiencies were excluded from the study.
The underlying causes of SMA in humans may include one or
more of the following mechanisms: (1) the clearance and/or
destruction of infected RBCs, (2) the clearance of uninfected
RBCs, (3) erythropoietic suppression and dyserythropoiesis. Each
of these mechanisms has been implicated in both human and mouse
malarial anemias (Table 3), but their relative contribution between
the species is likely to differ. In the remainder of this review, the
pathophysiological mechanisms of human and mouse malarial
anemia will be discussed, highlighting similarities and differences.
Loss of infected erythrocytes
During infection there is obvious loss of infected erythrocytes
through parasite maturation as well as through recognition by
macrophages. The pathways of phagocytic clearance for both
humans and mice are summarized in Table 3 (see Casals-Pascual
and Roberts37 for further discussion).
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BLOOD, 1 JULY 2007 䡠 VOLUME 110, NUMBER 1
LAMIKANRA et al
Table 1. Key rodent malaria infections with features of anemia
Plasmodium species/
parasite strain/clone
Mouse strain
Features of infection
Features of anemia
Reference no.
P chabaudi chabaudi
AS, CB, AJ, ER
C57BL/6 mice
Nonlethal
Acute anemia with extravascular hemolysis
Sequestration of mature iRBCs
A/J
Lethal
36, 66, 82
followed by reticulocytosis after peak
parasitemia
Acute and rapidly progressive anemia
66
Acute anemia
63, 65
Sequestration of mature iRBCs
P berghei
ANKA
C57BL/6 and CBA/J
Lethal
Cerebral syndrome
ANKA
BALB/c and DBA/2
Some sequestration of mature iRBCs
Inadequate reticulocyte response
Lethal, but also drug induced chronic
Chronic anemia in semi-immune mice
57
Anemia in splenectomized rats
119
56, 120
infection
No cerebral syndrome
P berghei
Rat
Lethal
BALB/c SCID
Nonlethal in BALB/c
Invades only reticulocytes
Sequestration of iRBCS in cerebral vessel
Premature removal of RBC
Lethal cerebral syndrome sequestration of
Can invade RBCs of all ages; acute anemia
112
Inhibition of erythropoiesis
121
P yoelii
17X
Increased parasitized RBC rigidity
17XL
BALB/c
iRBCS in cerebral vessel
P vinckei
BALB/c
Lethal
For more detailed information of mouse models of malaria infection, including immune responses and other pathology, see Lamb et
It is clear that similar mechanisms exist for the clearance of
infected erythrocytes in humans and mice. However, the removal
of infected erythrocytes in humans with parasitemias of less than
1% is unlikely to have a significant impact on the degree of anemia.
This removal, therefore, may prove more pertinent for the onset of
anemia in individuals suffering from an acute infection, in particular children where parasitemias are frequently greater than 10%.
Since malaria infections in mice often attain high parasitemias with
intravascular hemolysis of infected erythrocytes,38 they may provide suitable models to study the factors that contribute to the
pathology of anemia during acute falciparum infection.
Loss of uninfected erythrocytes
During human malaria infection, many uninfected red cells are
destroyed, in the spleen and quite possibly the liver, and their
destruction has been identified as the major contributor to malarial
anemia.39-41 Both mathematical modeling and clinical observations
suggest that 10 times as many uninfected RBCs are removed from
the circulation for each infected erythrocyte.40 Although few direct
measurements of red cell survival have been made in human
infections, reduced half-life of normal erythrocyte and increased
clearance of heat-treated erythrocytes have been demonstrated in
patients with malaria, consistent with these observations.39,42
The activity and the number of macrophages are also
increased during human malarial infection, and may therefore
al31
and Langhorne et al.38
contribute to the increased removal of uninfected cells.43-46 The
increased clearance of uninfected erythrocytes is due not only to
the activation of splenic macrophages but also to extrinsic and
intrinsic changes to the red blood cells that enhance their
recognition and phagocytosis. First, uninfected RBCs have a
reduced deformability leading to enhanced clearance in the
spleen. The mechanism responsible for the loss of deformability
is not completely understood. Increased oxidation of membranes in uninfected erythrocytes has been shown in children
with severe P falciparum malaria, and the ongoing inflammatory
insults associated with acute malaria (proinflammatory cytokines), or direct effect of parasite products have been shown to
cause loss of RBC deformability.44,47,48 Intriguingly, a severe
reduction in red cell deformability is also a strong predictor for
mortality measured on admission, both in adults and children
with severe malaria.49,50 Second, the deposition of immunoglobulin and complement on uninfected RBCs may enhance receptormediated uptake by macrophages (Table 3).
Parasite products that may be part of the immunoglobulinantigen complexes deposited on uninfected RBCs include the
P falciparum ring surface protein 2 (RSP-2). This protein, expressed shortly after merozoite invasion of RBCs, mediates
adhesion of iRBCs to endothelial cells.51,52 RSP-2 is also deposited
on uninfected RBCs and the opsonization of these RSP-2–bearing
uninfected RBCs provides a mechanism of removing uninfected
Table 2. Characteristics of disease during infection with P falciparum– and plasmodia-infecting mouse strains
Mouse
Parameter
Parasitemia, %
Hematocrit level, %
Hemoglobin concentration, g/dL
Erythropoietin, mU/mL
Human
P bergeii/Balb/c*
P chabaudi/A/J
2.672
15.7106
0.957
50–60109
12.972
NR
NR
10–15109
472
⬍ 5106
55% of baseline57
503372
1000106
NR
NR
1000–3000109
Representative values for parameters measured in patients who present with SMA are given for comparison with values obtained from a sample of studies in mice. For a
more detailed study on the changes in erythropoietin and severity of anemia during infection with P falciparum see Casals-Pascual.72
NR indicates not reported.
*Hb levels reported in this study were given as a percent of baseline values determined in noninfected mice.
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BLOOD, 1 JULY 2007 䡠 VOLUME 110, NUMBER 1
MALARIAL ANEMIA IN MICE AND HUMANS
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Table 3. Pathological features of P falciparum and mouse malarial anemia
References
Mechanism
Parameters
Human
Mouse
Clearance of iRBCs
Rigidity
Parasite Ag in iRBCs
122
120
Opsonization
Parasite specific Abs and complement
52, 123, 124
128-130
Band 3–specific Abs
125
Nonopsonization
Macrophage activation
126
131
Pitting
Deformability of RBC membrane by RESA
127
132
Opsonization
Immune complexes and CD35
133-136
Not determined
Nonopsonization
Macrophage activation
44
57
Rigidity
RSP-2 antibodies
53
Not identified
Oxidative stress
47, 137, 138
56
Quinine, mefloquine G6PD deficiency
29, 30
57
Haptoglobin
139, 140
40
Erythroid genes
115
116
High TNF:IL-10
78, 79
81
High MIF
88
87
Low IL-12
89
85
GPI
98
97
Hz
71
88
Abnormal precursor morphology
Eg, cytoplamsic bridging
59
Not observed
Insufficient reticulocytosis
Cell cycle arrest
61
63
Changes in BM precursor numbers
Decreased BFU-Es
141 acute disease
63
Decreased CFU-Es
None reported
142
Splenic erythropoiesis
None reported
65, 66, 112
Hepatic erythropoiesis
None reported
143
Clearance of uninfected RBCs and erythroblasts
Intravascular hemolysis
Hemoglobinemia and Hemoglobinuria
Suppression of erythropoiesis
Host genotype
Cytokines
Parasite products
Dyserythropoiesis
Extramedullary erythropoiesis
The etiology of anemia based on observations made during the course of disease is compared for P falciparum and mouse malaria infections.
RBC indicates red blood cell; iRBC, infected red blood cell; Ag, antigen; Abs, antibodies; RESA, ring-infected erythrocyte surface antigen; RSP-2, ring surface protein 2;
TNF, tumor necrosis factor ␣ ; IL, interleukin; MIF, macrophage inhibitory factor; GPI, glycophosphatidylinositol; HZ, hemozoin; BM, bone marrow; BFU-E, burst forming unit
erythroid; and CFU-E, colony forming unit erythroid.
RBCs. Indeed high levels of these antibodies that facilitate
complement-mediated phagocytosis of cells expressing RSP-2 are
found in sera from immune adults and children with severe anemia.53
This antigen is also present on the surface of erythroblasts in bone
marrows of P falciparum–infected patients, indicating that clearance or
damage to circulating or developing erythroid cells by RSP-2 and
anti–RSP-2 could contribute to the development of SMA.
Due to the high level of parasitemia, it may appear that the
clearance of uninfected RBCs for the development of anemia is less
significant in mice than in the majority of human malaria infections. However, in P chabaudi and P berghei infections the degree
of anemia is not always related to peak parasitemia,54,55 and
premature removal of uninfected RBCs has been shown in P yoelii
infection. Interestingly, immunoglobulin-mediated removal of erythrocytes in this infection was not implicated, but rather it was
thought that abnormalities in the erythrocytes themselves was
responsible.56 It remains to be determined whether removal of
RBCs via immune complex deposition takes place in mouse
infection, and the parasite product RSP-2 has not yet been
identified in rodent parasites. So far it seems that rodent models in
this respect may be representative of acute human infections only
where removal of uninfected RBCs is independent of opsonization.
However, this is clearly an area where further research is needed.
More recently, a model of chronic anemia has been developed
where P berghei ANKA–infected semi-immune rodents show that,
although parasitemia remains less than 1%, there is a 5- to 10-fold
increase in the clearance of uninfected RBCs.57 In this study,
clearance of uninfected RBCs was delayed in mice depleted of
macrophages supporting the view that removal of uninfected RBCs
is an important factor in anemia. Moreover, macrophage activation
was dependent on CD4⫹ T cells. This model could therefore
represent one feature of chronic human infection where removal of
uninfected erythrocytes contributes to the severity of anemia.
Erythropoietic suppression and dyserythropoiesis
Normal erythropoiesis (as described in Figure 2) is perturbed
during malaria infection. The earliest observations of reduced
erythropoiesis in acute human malaria were made more than 60
years ago where reticulocytopenia was observed in P vivax and
P falciparum malaria infection followed by reticulocytosis after
parasite clearance.58 Later, it was demonstrated that low reticulocyte counts in Thai patients with malaria was accompanied
by suppression of erythropoiesis (reviewed in Casals-Pascual
and Roberts37).
Bone marrow aspirates taken from Gambian children with acute
anemia revealed that despite an increase in cellularity no significant
difference in the total number of erythroblasts was observed when
compared with uninfected patients, providing evidence for a
suppressed erythroid response. Children who presented with chronic
anemia (parasitemia ⬍ 1%) had higher levels of erythroid hyperplasia and dyserythropoiesis59,60 Dyserythropoiesis or morphologically and/or functionally abnormal production of RBCs was
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22
LAMIKANRA et al
BLOOD, 1 JULY 2007 䡠 VOLUME 110, NUMBER 1
Figure 2. Human and murine erythropoiesis. At birth, erythropoiesis
occurs throughout the human skeleton, although over time hematopoietic
activity is confined to the sternum and pelvic region of most adults.
Likewise, in adult mice the bone marrow is the major organ, with the
majority of hematopoietically active cells typically present in the femur and
tibia, though this is dependent on the age and strain of the mouse.
Erythropoiesis from the multipotent hematopoietic stem cell (HSC) through
to the mature red blood cell is shown to allow comparison of human and
mouse cell surface phenotypes. The time at which these markers are
expressed and lost at the cell surface is very similar between species
indicating that as a first approximation the mechanisms used to control cell
expansion, differentiation, and removal of precursors may not differ
greatly. Developing erythroid cells respond to signals from stromal cells of
the bone marrow or spleen. Erythroblasts are organized into erythroblastic
islands that consist of macrophages surrounded by developing erythroid
precursors.144,145 Macrophages provide many of the cellular mediators that
control erythropoietic activity: GM-CSF, IL-3, and stem cell factor (SCF)
generate colony-forming unit erythroid macrophage-granulocyte
megakaryocyte (CFU-GEMM) and burst-forming unit erythroid (BFU-E),
whereas TGF-␤, TNF-␣, and MIP1-␣ inhibit cell cycle activity146 and
BFU-E development. Other factors that negatively regulate numbers
include proapoptotic activity initiated by interaction of the Fas receptor
(CD95) with Fas ligand (CD95L).147,148 Expression of caspases also
results in cleavage of GATA-1 and loss of its antiapoptotic activity.148
Secretion of Epo induces the expansion of colony-forming unit erythroid
(CFU-E) and initiates differentiation through a number of erythroid-specific
events. SCF and Epo synergize to drive the proliferation of human
erythroid progenitors and precursors150,151 and induce anti-apoptotic
activity.152,153 In human and mouse erythropoiesis, levels of the transferrin
receptor (CD71) peak when the highest transport of transferrin-bound iron
is required for synthesis of heme from protoporphyrin. During erythroid
precursor maturation an increase in expression of glycophorin A (gpA) in
humans or Ter119 in mice is coupled with a drop in CD71 expressed at the
cell surface. This loss of CD71 indicates reduced proliferation and heme
synthesis with continued differentiation into reticulocytes.
demonstrated by cytoplasmic vacuolation, stippling, fragmentation, intercytoplasmic bridges, nuclear fragmentation, and
multinuclearity. This coincided with reduced reticulocytosis indicating functional disruption of RBC output from the bone marrow59,60
(Figure 3). In a smaller study of 6 children with chronic disease, an
increased proportion of polychromatic erythroblasts in the G2
phase of division was observed.61 Treatment of these patients
with antimalarial drugs increased reticulocyte numbers, which
pointed to P falciparum as the cause of dyserythropoiesis and
ineffective erythropoiesis.
In the mouse, both lethal and nonlethal malaria infections
induce ineffective erythropoiesis, with alterations in erythropoietic
progenitor and precursor populations, as well as in the sites of
erythropoiesis (Figure 3). In contrast to the human studies cited, a
decrease in mouse bone marrow cellularity of between 40% to 75%
of normal levels is seen at peak parasitemia or death, whichever is
reached first,62-65 with reductions in cellularity proportional to the
severity of infection.54,63,66 However, despite these discrepancies
with the reported pathology in human infection, reports of only a
minimal reduction in the total number of BFU-Es, and at best only
a modest increase in CFU-Es in mice,63-66 suggest that the bone
marrow is unable to compensate for RBC loss in both humans and
mice through increased erythropoiesis during the acute phase of
infection. At present there are no studies reporting the production
of dyserythropoietic erythroblasts during mouse malaria infection,
most probably because there are few chronic infection models.
Dyserythropoiesis has been observed only in chronic human
infections, thus future studies on the production of abnormal
erythroblasts in the newly described chronic model of P berghei57
may help elucidate the mechanism by which this occurs.
A parasite by-product of hemoglobin digestion, hemozoin, may
have a role in the impaired erythroid development through its
effects on human monocyte function. Hemozoin reduces human
macrophage oxidative burst activity, prevents up-regulation of
activation markers,67,68 and also stimulates the secretion of biologically active endoperoxides from monocytes, such as 15(S)hydroxyeicosatetraenoic (HETE) and 4-hydroxy-nonenal (4-HNE)
through oxidation of membrane lipids,69,70 which may effect
erythroid growth.71 Macrophage dysfunction could also disrupt the
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BLOOD, 1 JULY 2007 䡠 VOLUME 110, NUMBER 1
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Figure 3. Direct and indirect effects of parasite on the development of malarial anemia. Severe malarial anemia is characterized by destruction of infected red blood cell
(iRBC) following schizogony and clearance of both iRBCs and uninfected RBCs. During malarial infection, changes in membrane protein composition occur and the resultant
immune complexes of RBCs, Ag, and immunoglobulin (Ig) (eg, RBC:RSP2:Ig) are cleared by macrophages to the spleen where they become activated (see Table 3 for more
examples). Pigment-containing macrophages may release inflammatory cytokines and other biologically active mediators such as hydroxy-nonenal (HNE). It is possible that
malarial pigment or other parasite products may have a direct inhibitory effect on erythropoiesis. Inhibition of erythropoiesis may be at one or more sites in the growth and
differentiation of hematopoietic progenitors. Both indirect and direct effects may cause suppression of the bone marrow and spleen resulting in inadequate reticulocyte counts
for the degree of anemia. The mechanisms of insufficient erythropoiesis in murine malaria have been summarized in Chang and Stevenson.154 Blue box indicates
demonstrated in human infection; pink box, demonstrated in mouse infection; yellow box, demonstrated in both human and mouse infections. Hz indicates hemozoin; GPI,
glycophosphatidylinositol anchors of merozoite proteins; Epo, erythropoietin; Epo-R, erythropoietin receptor; M⌽, macrophage; RSP-2, ring surface protein-2; and Ig,
immunoglobulin. Figure modified with permission from Springer Science Business Media, Heidelberg, Germany.
function of erythroblastic islands in which macrophages support
terminal differentiation of erythroblasts in the bone marrow.
Hemozoin and TNF-␣ also have additive effects on erythropoiesis in vitro, and in a clinical study hemozoin-containing macrophages and plasma hemozoin were associated with anemia and
reticulocyte suppression.72 Moreover, bone marrow sections from
children who died from severe malaria show a significant association between the quantity of hemozoin (located in erythroid
precursors and macrophages) and the proportion of erythroid cells
that was abnormal. These findings are consistent with a direct
inhibitory effect of hemozoin on erythropoiesis and therefore
warrant further investigation. Disappointingly, however, there has
been little focus on the role of hemozoin on erythropoiesis during
mouse malaria infection, where effects of hemozoin-induced
suppression of erythropoiesis could be dissected in an in vivo
setting. Clearly hemozoin present in bone marrow may have a role
in mice, as the efficient reticulocyte response is not observed until
there is parasite clearance.55,66
Cytokine suppression of erythropoiesis. During the acute
phase of both human and mouse infections there is a strong
inflammatory response, which results in increases in TNF-␣ and
IFN-␥.73-75 TNF-␣ inhibits all stages of erythropoiesis,76 and IFN-␥
works with TNF␣ to inhibit erythroid growth and differentiation by
up-regulating expression of TRAIL, TWEAK, and CD95L in
developing erythroblasts.77 However, in a nonlethal P chabaudi
(AS) infection of C57BL/6 mice, neutralization of TNF-␣ or IFN-␥
has no effect on in vitro erythropoiesis.74 While severe disease in
children is associated with elevated levels of proinflammatory and
anti-inflammatory cytokines, the severity of anemia seems to be
dependent on levels of TNF-␣ relative to its regulator, the potent
anti-inflammatory cytokine IL-10. Several clinical studies have
demonstrated that a low ratio of plasma IL-10/TNF-␣ is associated
with SMA in young children.78,79 Furthermore, a number of
polymorphisms in the human TNF-␣ promoter show greater
association with anemia than with cerebral malaria.80 The IL-10/
TNF-␣ ratio is also important in mice where IL-10 knock-out mice
infected with P chabaudi display increased anemia,81 which is
reversed following TNF-␣ neutralization in vivo.82 It is therefore
conceivable that in both humans and mice, IL-10 may protect
against bone marrow suppression and erythrophagocytic activity
induced by TNF-␣ and/or mitigate other proinflammatory stimuli.
Many other proinflammatory cytokines such as IL-12, IL-18,
and migration inhibitory factor (MIF) have also been implicated in
the pathogenesis of anemia in malaria. In humans, the secretion of
IL-12 and IL-18 from macrophages induces production of IFN-␥
from natural killer (NK), B cells, and T cells,83 while MIF is
produced by activated T cells and macrophages and inhibits the
anti-inflammatory activity of glucocorticoids (for review see Clark
and Cowden84).
IL-12 is present at higher levels in nonlethal, compared with
lethal, infections of P chabaudi, suggesting that this cytokine may
be a stimulator of erythropoiesis.85,86 Conversely, with elevated
levels found during infection, MIF has been shown to suppress
hematopoiesis,87 and more recently P chabaudi infection of MIF
knock-out mice resulted in a less severe anemia with improved
development of erythroid progenitors in the bone marrow.88 In this
latter study, a hyperparasitemic model of malaria (P chabaudi AS in
Balb/c) was used. However the levels of parasitemia, TNF-␣, and
IFN-␥ in wild-type and knock-out mice were equally raised,
therefore indicating a direct effect of MIF on erythroid development during the acute phase of disease.
The association of IL-12 with severe falciparum malaria is less
clear. While some studies observe moderate increases in IL-12 and
IL-18 in patients with severe anemia,83,89 others report decreases in
IL-12 in patients with severe malaria (Hb of ⬍ 75 g/L [7.5 g/dL])
compared with uncomplicated controls (Hb of ⬎ 100 g/L [10 g/dL]), or
no significant increases in patients with severe disease compared with
uncomplicated malaria.90,91 In these last 2 examples, anti-inflammatory
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24
LAMIKANRA et al
cytokines such as TGF-␤ or IL-10 were also reduced in patients
with severe disease. In contrast, patients with acute disease and
elevated levels of IL-12 had marked increases in IL-10.83 Since the
majority of patients with anemia in this last study had average Hb
levels of 90 g/L (9 g/dL) it is possible that, as with mice, increases
in IL-12 are associated with reduced severity of SMA. The data on
serum levels of MIF in patients with malaria are, however,
consistent with its role as a hematopoietic suppressor in mice: MIF
concentrations in those with moderate anemia are decreased,89 and
MIF is elevated in patients with more severe anemia.90
These observations, in both human and mouse infections, show
the complexity of cytokine responses, and also highlight the
importance of a balance between proinflammatory and antiinflammatory cytokines, which can either be protective or detrimental to the host. Understanding the role of these cytokines will
require more data from adequately powered studies to enable use of
more sophisticated multivariate analyses that may allow for
intricate interactions between each factor. In addition, significant
similarities do indeed exist between humans and mice, and the
ready availability of gene knock-out mouse models, for example,
will allow for more in-depth analysis of proinflammatory and
anti-inflammatory mechanisms without the confusion of human
genetic variability.
A parasite product found in plasma during human and mouse
infections that may be implicated in the proinflammatory cytokine
effects on SMA is the glycophosphatidylinositol (GPI) anchor of
the merozoite proteins, MSP-1, MSP-2, and MSP-4.92 GPIs are
likely to contribute to malarial anemia since they can induce the
release of TNF-␣ from human macrophages,93 which could contribute to the pathology of SMA. More specifically, it has recently been
demonstrated that the proinflammatory response from human
monocytes is through interaction of GPIs with TLR2, and to a
lesser extent TLR4.94 The role of GPI-induced anemia in mice has
not been studied directly. The injection of crude infected RBC
lysate into mice does result in a transient decrease in the number of
circulating RBCs,95 which is probably through the induction of host
inflammatory responses,96 however this could be the effect of a
range of other parasite products as well as GPI. Purified GPI
immunization of mice in one study did result in reduced cerebral
pathology and fatality, however effects on SMA were not reported.97 Further analysis of GPI-induced effects in mouse models
of malaria to investigate a similar mechanism in humans would be
of both academic and therapeutic interest because antibodies
specific to GPIs are found in sera of adults from endemic regions in
Kenya, but at reduced levels in children who, in general, have more
severe disease and malarial anemia.98
A product discussed earlier, hemozoin, may also be more
intimately linked to an innate immune response, and thus proinflammatory cytokine release, than previously thought. In humans,
synthetic pigment induces expression of TNF-␣, which has been
linked to the ability of hemozoin to induce the metalloproteinase
MMP-9,99-101 and relatively recent studies in mice have suggested
that hemozoin stimulates an innate proinflammatory response102
via a MyD88-dependent TLR9 pathway.103
Erythropoietin. A fall in Hb and subsequent reduction in
oxygen tension should stimulate elevated levels of erythropoietin
(Epo) in patients with SMA. The clinical evidence for appropriately raised levels of Epo in malaria is somewhat contradictory.
Studies in adults from Thailand and Sudan have suggested that the
Epo concentration, although raised, was inappropriate for the
degree of anemia.104,105 However, several studies of malaria in
African children suffering from malarial anemia have shown
BLOOD, 1 JULY 2007 䡠 VOLUME 110, NUMBER 1
appropriately raised Epo concentrations.25,106-108 In fact, the Epo
levels in malarial anemia are more than 3-fold higher when
compared with anemic children without malaria.72 It is possible
that ineffective or inadequate Epo synthesis does contribute to
malarial anemia in some settings, possibly related to age, ethnic
origin, or presentation of the patient. However, in African children
with malaria, Epo synthesis is indeed elevated more than expected
and it is more likely that a reduced response to Epo, not an
inappropriately low level of Epo, is the more significant contribution to pathology.
Similarly, in mice, P chabaudi AS infection of resistant
C57BL/6 and susceptible A/J strains results in anemia despite
increases in serum Epo.109 However, the increase in Epo, albeit
driving a somewhat blunted reticulocyte response, is a crucial
determinant of the outcome of infection. Neutralization of Epo
transforms P chabaudi AS infection in normally resistant C57BL/6
mice into a fatal infection. Intriguingly, induction of reticulocytosis
by exogenous Epo prior to infection enhanced parasite multiplication and resulted in lethal infection. However, timely induction of
reticulocytosis shortly after infection could alleviate malarial
anemia and increase survival of A/J (susceptible) mice.55
Thus, in both human and mouse malaria infections, increased
serum Epo appears essential for recovery, despite the possibility of
an attenuated bone marrow response to this growth factor. Clearly,
more extensive human studies are required to investigate the
kinetics of erythrocyte production in response to elevated Epo
during infection. However, a detailed phenotypic analysis of the
abnormalities in erythropoiesis during the rodent P chabaudi
infection may provide an insight to this mechanism, which has
revealed that not only is Epo-induced proliferation of early
erythroblasts suppressed, but also terminal differentiation and
maturation of TER119⫹ erythroblasts is impaired.110 Perhaps
surprisingly, these abnormalities of erythropoiesis were accompanied by neither an increase in apoptosis nor dysregulation of the
cell cycle, suggesting that serum Epo is increased appropriately but
that a reduced response to Epo is responsible for an insufficient
erythrocyte output.
Hematinic deficiency. Although dietary deficiencies are widespread in malaria-endemic regions, the influence of reduced folate
and iron levels is not thought to be a major contributor to
dyserythropoiesis seen during SMA.60 However dysregulation of
iron metabolism may contribute to the severity of disease in
children that present with SMA. The peptide hormone hepcidin has
been implicated in mediating anemia of chronic disease or inflammation by reducing the availability of iron stores for erythropoiesis.111 Hepcidin is regulated by proinflammatory mediators such
as IL-6, which is elevated in both murine infections and in patients
who present with severe falciparum malaria.38,91 To date, there are
no reports that describe the association of elevated hepcidin with SMA.
Extramedullary hematopoiesis. One substantial difference in
human and mouse responses to malarial anemia is that in mice the
marked decrease in bone marrow cellularity appears to be compensated by increased erythropoietic activity in the spleen (Figure 3).
However, to date there are no studies that have investigated
extramedullary erythropoiesis during P falciparum infection. In
mice, massive splenomegaly is observed with cellularity increasing
20-fold at peak parasitemia compared with that of naive animals.64,81 This rise is reflected in greater erythroid progenitor
populations with up to an 8-fold increase of BFU-E and 100-fold
increase of CFU-E total numbers in the spleen.65,66 Interestingly,
there is a strong correlation between the severity of disease and the
observed increases in splenic erythropoiesis. Lower rises in BFU-E
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BLOOD, 1 JULY 2007 䡠 VOLUME 110, NUMBER 1
MALARIAL ANEMIA IN MICE AND HUMANS
and CFU-E populations are seen in fatal infections, when compared
with nonfatal infections, which strongly suggests that a marked
splenic erythropoietic response is required for survival in mice.54,112
It is unknown whether this is relevant to human studies because
although splenomegaly is also observed in human patients with
severe anemia, this has been primarily attributed to increased
sequestration and erythrophagocytosis of infected and uninfected
RBCs113,114 (Figure 3). However, extramedullary hematopoiesis
commonly occurs in other conditions such as thalassemia in
both humans and mice, and it would therefore be important to
explore the erythropoietic role of the spleen in future human
malaria studies, since if this is the case then the mouse model
gains in relevance.
Finally, it should be noted that microarray analysis of peripheral
responses to human and mouse malaria infection could prove
extremely useful. One human study has allowed for some validation of clinical observations through the description of the gene
expression profiles in children with severe malaria and during their
convalescence.115 In this case, a positive correlation between
neutrophil counts and increased expression of genes activated in
the innate immune response as well as an inverse relationship
between reticulocyte count and expression of genes associated with
hemoglobin synthesis was observed. The advantage of a rodent
model for SMA would be that a more complete study of bone
marrow and splenic erythrocytic responses to malaria infection
is possible, and several studies analyzing different organs from
infected mice have described some promising results, such as a
reduction in the level of gene transcripts involved in erythropoiesis and erythroid cell survival, during the early stages of
infection.116-118 These preliminary observations reveal that this
technology is capable of extensive analyses in both humans and
mice. Future studies should be considered because, as well as
being able to identify the similarities and differences of the
human and mouse peripheral response, microarrays may also
facilitate the development of therapeutics.
25
etiology of disease include those that use P chabaudi and P yoelii.
However, the causative factors of SMA in chronic infection in
humans are less clear and have not been extensively investigated in
mice. In addition to the chronic P bergei model of rodent malaria
mentioned previously, more chronic models of malaria infection
with persistent but low parasitemias need to be developed. During
the course of a chronic infection, there would be impaired
clearance of parasite products (eg, RSP2, Hz, and GPI), and their
accumulation may together or individually contribute to the
chronic nature of SMA. Future studies of the longer term effects of
parasite products on cytokine regulation and hematopoiesis in mice
may be valuable in elucidating the mechanism involved in suppression of RBC production. Such studies coupled with in vitro
investigations of the effects of parasite products on human
hematopoietic cells will allow us to determine the stages of
erythropoiesis involved and will increase our understanding of the
etiology of SMA. However, it will be essential to link these animal
and experimental data with studies in patients with malaria aimed
at understanding not only the mechanisms leading to severe anemia
but also their relative importance in different clinical settings.
Already, from the studies summarized in this review on both mouse
and human SMA, several interesting hypotheses await further
clinical investigation and may lay the foundation for novel
interventions to prevent or treat severe malarial anemia.
Acknowledgments
This work was supported by the National Blood Service, the Howard
Hughes Medical Institute (A.A.L. and D.J.R.), the MRC (D.B., A.P., and
J. L.), and the EU BioMalPar NoE (A.A.L., D.J.R., D.B., A.P., and J. L.).
We would like to thank Kevin Marsh, Paulo Arese, Suzanne
Watt, and Bill Wood for helpful discussions and critical thoughts.
The research was carried out in part at the NBS-Oxford Center and
benefits from NHS R&D funding.
Authorship
Summary
In summary, it is possible to identify specific similarities and
differences between disease pathology during P falciparum infection in humans, and infection with specific strains of Plasmodia in
mice. The mouse is particularly useful for studying anemia
associated with the acute phase of infection. One of the key
similarities at this stage is that the erythropoietic response to Epo
does not correct the deficit in hematocrit caused by hemolysis and
sequestration of RBCs and that this is associated with abnormalities in the bone marrow. In acute disease the imbalance between
proinflammatory and anti-inflammatory mediators may be the main
cause of dyserythropoiesis. Mouse models that may represent this
Contribution: A.A.L. and D.B. contributed to design and content of
paper, to review of literature, and to writing the draft; A.P. and
C.C.-P. contributed to content of the review; J.L. and D.J.R.
critically reviewed text and edited tables and figures.
A.A.L. and D.B. contributed equally to the review.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Jean Langhorne, National Institute for Medical Research, The Ridgeway, London, NW7 1AA; e-mail:
[email protected]; and David J. Roberts, Nuffield Department of
Clinical Laboratory Sciences and National Blood Service Oxford
Centre, Oxford OX3 9BQ; e-mail: [email protected].
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From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
2007 110: 18-28
doi:10.1182/blood-2006-09-018069 originally published
online March 6, 2007
Malarial anemia: of mice and men
Abigail A. Lamikanra, Douglas Brown, Alexandre Potocnik, Climent Casals-Pascual, Jean Langhorne
and David J. Roberts
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