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Memórias do Instituto Oswaldo Cruz
Fundação Oswaldo Cruz, Fiocruz
ISSN: 1678-8060 EISSN: 1678-8060
Vol. 106, Num. s1, 2011, pp. 91-104
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Memórias do Instituto Oswaldo Cruz, Vol. 106, Special Issue, pp. 91-104
Original Article
Malaria-related
anaemia: a Latin American perspective
Juan Pablo QuinteroI,
VII; André Machado SiqueiraII , III; Alberto TobónIV;
Silvia BlairIV; Alberto MorenoV, VI; Myriam Arévalo-HerreraI,
VII; Marcus Vinícius Guimarães LacerdaII, III;
Sócrates Herrera ValenciaI, VII, +
ICaucaseco
Scientific Research Center, Cali, Colômbia
IIFundação de Medicina Tropical Dr Heitor Vieira Dourado,
Manaus, AM, Brasil
IIIUniversidade do Estado do Amazonas, Manaus, AM, Brasil
IVUniversidad de Antioquia, Medellin, Colombia
VEmory Vaccine Centre, Yerkes National Primate Research Centre, Atlanta,
GA, USA
VIDivision of Infectious Diseases, Department of Medicine, Emory
University, Atlanta, GA, USA
VIICentro Latino Americano de Investigación en Malaria, Cali,
Colombia
+ Corresponding author: sherrera@inmuno.org
Received 4 April
2011
Accepted 4 July 2011
Code Number: oc11145
Abstract
Malaria is the
most important parasitic disease worldwide, responsible for an estimated 225
million clinical cases each year. It mainly affects children, pregnant women
and non-immune adults who frequently die victims of cerebral manifestations
and anaemia. Although the contribution of the American continent to the global
malaria burden is only around 1.2 million clinical cases annually, there are
170 million inhabitants living at risk of malaria transmission in this region.
On the African continent, where Plasmodium falciparum is the most prevalent
human malaria parasite, anaemia is responsible for about half of the malaria-related
deaths. Conversely, in Latin America (LA), malaria-related anaemia appears to
be uncommon, though there is a limited knowledge about its real prevalence.
This may be partially explained by several factors, including that the overall
malaria burden in LA is significantly lower than that of Africa, that Plasmodium
vivax, the predominant Plasmodium species in the region, appears
to display a different clinical spectrus and most likely because better health
services in LA prevent the development of severe malaria cases. With the aim
of contributing to the understanding of the real importance of malaria-related
anaemia in LA, we discuss here a revision of the available literature on the
subject and the usefulness of experimental animal models, including New World
monkeys, particularly for the study of the mechanisms involved in the pathogenesis
of malaria.
Key words:
Plasmodium falciparum - Plasmodium vivax - malaria - anaemia -
haemoglobin - Latin America
Malaria is the
most important parasitic disease worldwide, causing 225 million clinical cases
and an estimated 781,000 fatalities annually, and represents a major global
public health problem (WHO 2010). Although four Plasmodium species have
been classically responsible for human malaria, Plasmodium falciparum has been the most prevalent overall, particularly in Africa (86%). On this continent,
the greatest mortality is associated with cerebral malaria and severe anaemia,
mostly in children less than five years of age, in malaria holoendemic areas
(Guerra et al. 2010). In sub-Saharan Africa, pregnant women are also at higher
risk of cerebral malaria and anaemia, which are consequently the major causes
of perinatal morbidity and mortality. Both of these malarial complications are
responsible for a great number of spontaneous abortions, stillbirths, premature
deliveries and low birth weight (Dicko et al. 2003).
Because of the
higher P. falciparum global prevalence, morbidity and mortality, most
research efforts on malaria pathogenesis have been focused on this species (Akhwale
et al. 2004). However, Plasmodium vivax represents the second most prevalent
species, responsible for an estimated 25-40% of the reported malaria clinical
cases (Westenberger et al. 2010). Until recently, there was a mistaken belief
that P. vivax was always a benign disease, however, there is growing
body of evidence of the high prevalence of severe and complicated P. vivax
malaria cases, including severe anaemia (Genton et al. 2008, Tjitra et al. 2008,
Kochar et al. 2009, Alexandre et al. 2010, Andrade et al. 2010). Additionally,
it is likely that the incidence of anaemia may be higher than what is currently
diagnosed. Multiple factors indicate that the public health relevance of P.
vivax may be more significant than was traditionally thought: (i) P.
vivax has a wider geographical range - potentially exposing more people
to the risk of infection, (ii) it is less amenable to control and (iii) most
importantly, infections with P. vivax can cause severe clinical syndromes
(Tjitra et al. 2008).
Approximately 170
million people live at risk of P. vivax and P. falciparum transmission
in 21 countries in Latin America (LA) and the Caribbean (Guerra et al. 2008,
2010). Nearly 60% of the malaria cases in the Americas are reported from Brazil
and the other 40% are reported from Colombia (14.2%), Peru (8.8%), Venezuela
(5.4%), Bolivia (1.9%) and Ecuador (1.1%). Caribbean cases include those reported
in Haiti (2.8%). Central American countries report the occurrence of malaria
cases as Guatemala (3.8%), Panama (0.4%) and Honduras (1.5%). In terms of malaria
species distribution, 74% of infections are caused by P. vivax, 25% by
P. falciparum and < 0.01% by Plasmodium malarie. All the species
together contributes a mortality estimated in less than 0.1% to the overall
mortality caused by malarial infections (WHO 2009).
The benefits of
a detailed knowledge of P. vivax transmission and its clinical burden
are identical to those of P. falciparum. The development of the Malaria
Atlas Project has shown that the global mapping of malaria is a fundamental
step to (i) understand the epidemiology of the disease on a global scale, (ii)
appraise the equity of global financing for malaria control and (iii) set the
basis for disease burden estimation. Although significant progress has been
made in P. falciparum mapping, in the case of P. vivax, such maps
have been developed only recently, making any strategic planning in LA more
difficult (Guerra et al. 2010).
To elucidate the
molecular mechanisms involved in the pathogenesis of malaria-induced anaemia,
this review address the malarial anaemia immune pathogenesis process and the
relevance of currently available experimental animal models, particularly New
World monkeys, which are susceptible to human malaria parasites (Alexandre et
al. 2010, Andrade et al. 2010).
Epidemiology
of malaria-related anaemia in LA - It has been estimated that nearly 50%
of the population, distributed in 21 countries of the American continents, is
exposed at some level to the risk of malaria transmission (Gusmao 1999). Of
these countries, Brazil and Colombia experience greater than 60% of the malaria
cases. In LA, malaria exhibits epidemiological characteristics that appear to
be particular to the region. There is an extraordinary parasite genetic differentiation
due to bio-geographic barriers such as the Andean ridge, which separates endemic
areas on the Pacific coast of the region from those in the Amazon and Orinoco
Basins.
In the case of
P. falciparum, there is substantial spatial and temporal heterogeneity
in the proportion of infections caused by each parasite population (Cortese
et al. 2002, McCollum et al. 2007). This has resulted in the isolation of parasite
populations and limited dispersion of mutations, such as those associated with
anti-malarial drug resistance in P. falciparum populations, which may
have consequences for malaria control strategies. Drug resistance associated
mutations that are common in the Amazon and Orinoco Basins have not been introduced
to the Pacific coast region (Bacon et al. 2009, Corredor et al. 2010). Additionally,
there is a dense forest, known as the Darien gap, which geographically separates
Central America from South America and maintains parasite populations that harbour
significantly different drug sensitivity profiles (Restrepo-Pineda et al. 2008).
Interestingly, communities in these distinct geographical areas correspond to
highly diverse ethnic groups (e.g., African descendants, native Indians and
mestizos) with critical genetic differences in their Duffy (Fy) blood groups,
which influence P. vivax malaria susceptibility (Hadley & Peiper
1997). As a consequence of this complexity, but also because of the limited
resources traditionally allocated to malaria research in this region, the epidemiology
of malaria, including the prevalence of anaemia in these areas, is still poorly
understood.
An exhaustive search
for studies addressing malaria-related anaemia in the 21 countries of LA known
to have malaria transmission has indicated that only 56 studies have been published
in this period. This represents the work spanning the more than 60 years since
the initiation of the Malaria Eradication Campaign. Twenty-four of the studies
reported anaemia and/or information on haemoglobin (Hb) levels in community-based
malaria patients (Table I), 18 studies were based
on reports of hospitalised malaria patients (Table
II) and 14 corresponded to cross-sectional surveys in malaria-endemic communities
(Table III). Additionally, 70% of the published
studies were contributed by only three countries: Brazil, Venezuela and Colombia,
significantly limiting the geographical distribution of the available information.
Unfortunately,
not only are studies scarce but they are also not comparable because (i) the
designs of the studies were variable, (ii) the populations studied were different,
(iii) the definition of anaemia was not universal, (iv) it is difficult to thoroughly
understand the history of the infection, as several of the studies were cross-sectional
and not prospective, (v) co-infections were frequently present, such as bacteraemia
or helminth infection and (vi) patients with haemoglobinopathies or glucose-6-phosphate
dehydrogenase (G6PD) deficiencies presented at different prevalence rates. Therefore,
although severe anaemia was reported in these studies, it is not possible to
determine its prevalence, which appears to be low regardless. These findings
indicate the need for better-designed studies of malaria-related anaemia that
assess not only its overall prevalence, but also its association with malnutrition
and with common co-infections and diseases, such as helminth infections, bacterial
infections and hepatitis.
Clinical spectrum
of anaemia in human subjects - The clinical manifestations of malaria depend
on multiple factors from the parasite, parasite-host interactions and host factors,
including socio-economic conditions. Some of the host factors that have been
studied more in-depth include immunity, particularly the production of pro and
anti-inflammatory cytokines, genetic traits, α
or β-thalassemia,
Fy phenotype, sickle cell traits and age. Parasite factors such as endemicity,
drug resistance, Plasmodium species, parasite multiplication rates and
antigenic polymorphism are of great relevance for anaemia development. Moreover,
social-geographical factors, such as access to treatment, cultural and economic
factors, health policies and transmission intensity greatly contribute to increased
risk of anaemia.
Malarial anaemia
is usually normocytic and normochromic (Phillips et al. 1986, Bashawri et al.
2002), without spherocytes or schistocytes. However, the anaemia associated
with malaria can also be microcytic and hypochromic due to the high frequencies
of haemoglobinopathies and iron deficiency in endemic countries (Bashawri et
al. 2002).
Another key feature
of malarial anaemia is the presence of inadequate reticulocytosis, despite the
degree of anaemia. In acute uncomplicated malaria due to P. falciparum,
the haematocrit may be normal during the first 24 h after the onset of fever,
but afterwards there can be a progressive fall in the haematocrit level (Wickramasinghe
& Abdalla 2000) despite the initiation of anti-malarial treatment (Phillips
et al. 1986) and even in the absence of parasites in the blood smear (English
et al. 2002) or the administration of blood transfusions.
During malaria
infection, there are soluble derivatives released by the parasite that induce
bone marrow (BM) dysfunction. These derivatives are therefore implicated in
the pathogenesis of malarial anaemia (Silverman et al. 1987, Miller et al. 1989,
Jootar et al. 1993). This is reinforced by the observation that, as a consequence
of repeated infections or suboptimal treatment, children may be partially immunocompromised
and so asymptomatic during chronic P. falciparum infections. Despite
having very low Hb levels (Kurtzhals et al. 1999), these children display absolute
reticulocyte counts lower than expected for the degree of the anaemia (Wickramasinghe
& Abdalla 2000). These low counts might indicate some degree of BM dysfunction
(Kurtzhals et al. 1997). For P. vivax infection, it has been observed
that the decrease in Hb concentrations can be attributed to the activity of
the parasites. The destruction of erythrocytes is marked at the beginning of
the infection and erythrocytes do not return to pre-infection numbers in a short
period of time, despite the elimination of the infection. This can be primarily
explained by P. vivax invasion to reticulocytes, which prevents the establishment
of the normal erythrocyte population (Collins et al. 2003).
Immunopathology
- Although several mechanisms appear to participate in the generation of anaemia
in individuals acutely or chronically infected with malaria, the mechanisms
can nevertheless be grouped into two main categories: (i) destruction of cells
in the peripheral circulation and (ii) a reduction in or alteration of the production
of erythroid precursors. Although host genetics may exert some influence for
these two mechanisms, its role in anaemia pathogenesis is still poorly understood.
For instance, host genetic diversity may explain, to some extent, variations
in the frequency of anaemia when distinct areas are compared worldwide. The
Fy-negative genotype, which prevails on the Colombian Pacific coast, for example,
defines the higher prevalence of P. falciparum in that region, as compared
to other regions where P. vivax is more prevalent (Caicedo et al. 2009).
Likewise, there is evidence that FY*B/FY*X and FY*A/FY*X genotypes are associated
with low levels of P. vivax parasitism, which may favourably impact Hb
levels (Albuquerque et al. 2010). Recently, G6PD deficiency (Mediterranean type)
was shown to protect against P. vivax infection (Leslie et al. 2010);
however, protection by the African type, which is more prevalent in LA (Chagas
et al. 2009), has never been shown.
Peripheral destruction
of red blood cells (RBC) - An important part of the Plasmodium life
cycle occurs as an obligate intraerythrocytic parasite, where it differentiates
and multiplies at the expense of the host cell's nutrients up to the induction
of its burst. Each merozoite released either from the liver or from an erythrocyte
invades a new erythrocyte; in the case of P. vivax, its merozoites have
a preference for immature red cells (reticulocytes), whereas in the case of
P. falciparum, its merozoites invade erythrocytes of any age (Simpson et
al. 1999, Rayner et al. 2005). This parasite-specific invasion preference entails
the expression of receptors on the erythrocyte surfaces that are required for
an invasion. These include the Fy group antigens and reticulocyte-binding ligands
in the case of P. vivax (Galinski et al. 1992) or glycophorins A, B and
C, sialoglycoproteins expressed on human erythrocytes, in the case of P.
falciparum (JaŚkiewicz 2007). An obvious consequence of the parasite
multiplication and the periodic burst of schizonts is the rupture of infected
erythrocytes. Although this clearly contributes to the development of anaemia,
it does not appear to be sufficient to explain the levels of anaemia attained
in individuals exposed to the infection. It has been established that levels
of parasitaemia of > 50,000 parasites/µL are indicative of severe
falciparum malaria (WHO 2000). An infection level that corresponds to
the infection and destruction of approximately 1% of the total erythrocyte mass
could be easily replaced by erythropoiesis under normal conditions. However,
it seems that simultaneous to this mechanism, depuration of the parasitized
erythrocytes also occurs as a consequence of the phenomenon of erythrocyte rigidity.
This rigidity is induced by the transport of parasite antigens to the infected
erythrocyte membrane and is followed by the deformation of the membrane, opsonisation
by antibodies and complement and by macrophage activation (Wickramasinghe &
Abdalla 2000). However, in many cases, the severity of malaria anaemia does
not directly correlate with the degree of circulating parasitaemia (e.g. <
1%), though detected parasitaemia does not reflect the total parasite load,
as it does not take into account parasites sequestered in the microvasculature
(Nakazawa et al. 1995). Additionally, erythrocytes of malaria patients have
a decreased half-life compared to those of healthy individuals (Looareesuwan
et al. 1991). Moreover, epidemiological and mathematical models have shown that
between 8-12 non-parasitized erythrocytes may be destroyed for each Pf-RBC
parasitized (Jakeman et al. 1999, Price et al. 2001).
Although the precise
cause of the destruction of non-parasitized erythrocytes is unknown, several
mechanisms have been postulated: (i) the production of auto-antibodies against
the proteins that modify RBC membranes (Jakobsen et al. 1995), (ii) antibody-independent
phagocytosis of phosphatidyl-serine exposure, secondary to damage mediated by
reactive oxygen species (Bratosin et al. 1998, Serghides et al. 2003), (iii)
recognition of malarial antigens on infected erythrocytes by immunoglobulins
(Igs) and their further clearance by macrophages (Waitumbi et al. 2000), (iv)
complement-mediated phagocytosis and/or haemolysis (Ritter et al. 1993) and
(v) loss of complement regulatory proteins (CD35, CD55 and CD59) (Waitumbi et
al. 2000, Stoute et al. 2003). Furthermore, it has been documented that the
activities and absolute numbers of macrophages are increased during infection;
together with erythrocyte changes (decreased deformability and deposition of
Igs), this could assist in the depuration of non-parasitized erythrocytes during
infection (Mohan et al. 1995).
When dealing with
the poorly described P. vivax-induced anaemia phenomenon, another relevant
issue is the increasing body of evidence of P. vivax chloroquine resistance
in many endemic areas, including some regions of LA (Santana Filho et al. 2007),
which tends to increase peripheral parasitaemia for a longer period of time.
It has been demonstrated that in areas where chloroquine resistance has been
identified, severe disease (especially severe anaemia) is also frequent, which
raises the possibility of a causal effect (Price et al. 2009). Biomarkers of
resistance are urgently needed to validate this ecological association.
BM alterations
-The mechanisms of BM dysfunction induced by malaria appear to be multiple but
are still only partially known. The first observations of BM dysfunction during
malaria infection occurred over 60 years ago, when reticulocytopaenia was documented
in humans during P. falciparum and P. vivax infection. Afterwards,
it was shown that patients with acute P. falciparum infections had low
reticulocytaemia (or inappropriate reticulocytosis), which was accompanied with
suppression of erythropoiesis (erythroid hypoplasia) (Camacho et al. 1998).
Despite having increased cellularity in BM aspirates, there were no significant
differences in the total numbers of erythroblasts (Abdalla & Wickramasinghe
1998). These findings provided evidence of a decrease in the erythroid response
at the BM level. Children with chronic malaria, low parasitaemias (< 1%)
and severe anaemia display erythroid hyperplasia and dyserythropoiesis (Abdalla
et al. 1980, Wickramasinghe et al. 1989, Abdalla & Wickramasinghe 1998)
accompanied by ineffective erythropoiesis and decreases in circulating reticulocytes.
Inadequate production
of reticulocytes suggests insufficient erythropoiesis, which may be the result
of either hypoproliferative erythropoiesis or hyperproliferative but ineffective
erythropoiesis. Ineffective erythropoiesis is generally associated with intramedullar
destruction of erythroid precursors by erythrophagocytosis or dysplastic changes
of these precursors, which can be recognised by cytoplasmic vacuolation, abnormal
nucleus (bilobed), nuclear budding, formation of interchromatin and intracytoplasmatic
bridges and nuclear fragmentation.
It appears that
in acute and some chronic anaemia patients, there are two major forms of anaemia:
(i) anaemia with erythroid hypoplasia with or without dyserythropoiesis and
(ii) anaemia with erythroid hyperplasia and dyserythropoiesis. Acute malaria
infection in adults may be accompanied by a reduction in total erythropoietic
activity. In these cases, there may be normal BM or reduced cellularity with
erythroid hypoplasia. In cases of high parasitaemia, there may even be ineffective
erythropoiesis of the residual erythropoietic activity (hypoproliferative erythropoiesis).
Several studies
have documented a loss of precursor cells in the BM (Dörmer et al. 1983),
reduced use of iron by the erythrocytes and dysplasic changes in the BM (Knuttgen
1987). However, in other studies, no evidence of dyserythropoiesis was found
in children with acute P. falciparum infection (Das et al. 1999). Therefore,
it has been proposed that, in contrast to chronic malaria, dyserythropoiesis
plays a minor role in the pathogenesis of anaemia during an acute malaria infection
(Das et al. 1999, Jakeman et al. 1999). Some studies suggest that ineffective
erythropoiesis and dyserythropoiesis play greater roles (Abdalla et al. 1980,
Weatherall et al. 1983) in chronic malaria infection, which may be accompanied
by a severe anaemia characterised by an erythroid hyperplasia and dysplasia,
some degree of erythrophagocytosis and low levels of reticulocytes. In this
case, the dyserythropoiesis is directly related to malaria and is not caused
by deficiencies of folate, vitamin B12 or iron (Abdalla et al. 1984).
However, ineffective
erythropoiesis during malaria could develop through different mechanisms, such
as altered Hb synthesis in vitro and premature death of normoblasts (Srichaikul
et al. 1973, 1976).
Susceptible
populations - In malaria-endemic regions, the most susceptible populations
to suffer severe and complicated disease, including anaemia, are children <
five years of age and pregnant women. Although older children and adults still
suffer repeated malaria infections, the disease frequency and severity is progressively
reduced. This clinical immunity does not develop in areas of low endemicity
or seasonal exposure to parasites; therefore, the disease affects all groups
in these regions (Miller et al. 1994). Pregnant women, although previously clinically
immune, become more susceptible to developing the pathogenic processes that
affect both the mother and the foetus, and subsequently the newborn.
Two of the most
feared malaria complications that are associated with an increased mortality,
especially in children and pregnant women, are cerebral malaria and severe anaemia,
with mortality rates of 5.6-16% in children (Marsh et al. 1995) and approximately
6% in pregnant women (Granja et al. 1998, Menendez et al. 2000, Weatherall et
al. 2002). As mentioned, immunological factors and mechanisms appear to have
great relevance in the anaemia pathogenesis during a malaria infection. Beside
the role of the antibodies that are specific to malarial antigens and are exported
to erythrocyte membranes, the potential role of the erythrocyte-targeted auto-antibodies
and that of complement activation and cytokine imbalances are associated with
an increased anaemia severity in children with malaria. Pro-inflammatory cytokines,
such as tumour necrosis factor-alpha (TNF-α)
and interleukin (IL)-6, are elevated during an acute malarial infection (Kern
et al. 1989, Lyke et al. 2004) while anti-inflammatory cytokines, such as IL-10,
are substantially decreased (Kurtzhals et al. 1998, 1999, Akanmori et al. 2000).
Furthermore, elevated TNF-α
levels are associated with an increased anaemia severity in children with malaria
(Shaffer et al. 1991) and a low IL-10/TNF-α
ratio is associated with an enhanced anaemia severity, suggesting that the relative
expression of cytokines in the inflammatory milieu is an important determinant
of severe malarial anaemia (Othoro et al. 1999, Perkins et al. 2000). It has
also been observed that increased levels of TNF-α
are associated with a decrease in erythroid progenitor cells, decreased iron
uptake by erythrocytes, erythrophagocytosis of nucleated erythroblasts and dyserythropoiesis
(Phillips et al. 1986, Silverman et al. 1987, Clark & Chaudhri 1988, Miller
et al. 1989, Taverne et al. 1994). Moreover, recent studies show that hepcidin,
a 25-amino-acid protein produced in the liver, is associated with the anaemia
of inflammation in humans, where its production is increased 100-fold, resulting
in both an impaired iron uptake in the gut and iron sequestration in macrophages
(Ganz 2003, Means 2004).
Between 60-80%
of Hb is degraded during the intraerythrocytic cycle, releasing haemozoin (Hz)
and amino acids, which are used by the parasite to produce proteins. The presence
of Hz in the cytoplasm of polymorphonuclear leukocytes and monocytes appears
to be associated with the severity of the malarial infection, as it seems that
cytoplasmic Hz is more frequently found in the complicated malaria cases than
in the uncomplicated cases (Nguyen et al. 1995, Amodu et al. 1998, Lyke et al.
2003, López et al. 2004).
Experimental
animal models of malarial anaemia - In-depth haematological studies in humans
with malarial anaemia pose a number of ethical and technical challenges that
preclude invasive procedures, particularly BM analyses over the course of the
infection. The development of experimental animal models is therefore critical
for understanding the mechanisms involved in the pathogenesis of severe anaemia.
Although some molecular bases of malarial anaemia could be shared by several
Plasmodium species, experimental evidence suggests that species-specific
factors play significant roles. For example, a larger proportion of the non-infected
RBCs are removed by erythrophagocytosis in P. vivax-infected individuals
- it is estimated that ~32 non-infected RBCs are destroyed per every P. vivax-infected
RBC (Collins et al. 2003), compared to approximately eight non-infected RBCs
destroyed per every P. falciparum-infected RBC (Jakeman et al. 1999).
Four rodent malaria
parasite species (Plasmodium berghei, Plasmodium chabaudi, Plasmodium
vinckei and Plasmodium yoelii), have been extensively used to study
malaria pathogenesis, including anaemia, due to their distinctive erythrocyte
invasion profiles, which are similar to those observed with human parasites
(Lamb et al. 2006). However, several features, such as anaemia in the presence
of hyperparasitaemia and extramedullar erythropoiesis, which are frequently
observed in rodents, are rare events in human malarial infections (Silverman
et al. 1987, Yap & Stevenson 1992). Anaemia research in rodent models allows
immunological studies and manipulations that are more difficult in other animal
models, such as primates. Examples include in vivo depletion of macrophages
and CD4+ T cells, comparisons of resistant vs. susceptible strains,
experiments involving cytokine knockout mice, such as IL-10 (Linke et al. 1996)
and macrophage migration inhibitory factor-deficient mice (Stevenson et al.
2001, McDevitt et al. 2006). Non-human primate models appear to be more relevant
in LA, due to their abundance in the region and the availability of several
primate colonies.
New World monkeys
(Aotus and Saimiri) have been used extensively for vaccine trials
and drug testing using P. falciparum and P. vivax-adapted strains
(Collins 1992, Obaldia 2001, Herrera et al. 2002). Malaria semi-immune Aotus
monkeys immunised with merozoite vaccine candidates or exposed to P. falciparum
were protected from hyperparasitaemia, but were more likely to develop severe
anaemia after a second challenge (Egan et al. 2002, Jones et al. 2002). In this
experimental model, low Hb levels were associated with low reticulocyte counts,
suggesting that the ineffective erythropoiesis and removal of non-infected erythrocytes
are at least part of the aetiological factors involved (Egan et al. 2002). Aotus
monkeys that self-control parasite patency or that received anti-malaria treatment
exhibited a robust reticulocytosis, indicating a direct effect of the parasite
on erythroid progenitors. Interestingly, immunisation of Aotus monkeys
with the P. falciparum CIDR1α
domain of PfEMP1, a protein involved in sequestration, prevents the development
of anaemia after re-infection (Makobongo et al. 2006). Aotus also appears
to be a good model to study the role of hepcidin homeostasis. Although little
is known about the relationship between hepcidin and malarial anaemia, one study
developed in Colombia with the Aotus model showed that hepcidin levels
decreased throughout the experiment in malaria and mock-infected animals (Llanos
2008). Regardless of this finding, it remains an area for further research.
Methodologies have
been implemented to study the BM compartment in Aotus monkeys experimentally
infected with P. falciparum and P. vivax (Llanos et al. 2006).
Interestingly, on-going studies have confirmed that high numbers of normoblasts
are present in BM aspirates, suggesting that erythropoiesis is effective (unpublished
data) (Llanos 2008). However, the molecular mechanisms involved in severe anaemia
in semi-immune Aotus monkeys remain unknown (Egan et al. 2002).
Simian malaria
parasites have been a critical resource for understanding the biology of Plasmodium
(Brown & Brown 1965, Coatney 1968) for facilitating the development of anti-malarial
drugs (Omar et al. 1973) and for characterising the mechanisms involved in the
physiopathology of severe malaria (Davison et al. 1998). Unfortunately, comprehensive
investigations on malaria pathogenesis have not been addressed using these experimental
models (Galinski & Barnwell 2008). Plasmodium coatneyi and Plasmodium
fragile share with P. falciparum the ultrastructural features that
are involved in parasite sequestration and rosetting. Therefore, these parasite
species mimic clinical complications of cerebral malaria associated with P.
falciparum infections in humans (Kawai et al. 1993, Fujioka et al. 1994).
P. coatneyi infection in macaques has also been associated with placental
malaria, thrombocytopaenia, anaemia and disseminated intravascular coagulation
(Kawai et al. 1993, Sein et al. 1993, Nakano et al. 1996, Smith et al. 1996,
Davison et al. 1998, Collins et al. 2001, Moreno et al. 2007). Plasmodium
cynomolgi is phylogenetically related to P. vivax and shares its
capacity to produce hypnozoites (Krotoski et al. 1982). The patterns of relapses
described in P. vivax are also present in rhesus macaques exposed to
P. cynomolgi sporozoites, making this model ideal for studying the mechanisms
of chronic anaemia (Schmidt 1986). Comparative experiments using P. coatneyi
and P. cynomolgi in rhesus macaques are required to define whether the
molecular mechanisms underlying the pathogenesis of malarial anaemia are shared
between these two species. Unfortunately, such studies are restricted to primate
centres outside LA.
Conclusions
and perspectives - Beside the acknowledged importance of anaemia as a cause
of morbidity and mortality in Africa and other endemic regions, little is known
about its prevalence and burden in the malaria-endemic regions of LA. The few
studies reported from this region appear to indicate that the incidence of severe
anaemia is significantly lower than that reported from Africa or Asia. However,
considering that specific haematological changes associated with malaria infection
may vary with the level of malaria endemicity (Idro et al. 2006), nutritional
status (Friedman et al. 2005), demographic factors (Barcus et al. 2007), malaria
immunity (Langhorne et al. 2008) and the parasite species, it is essential to
study and characterise the epidemiology and mechanisms involved in malarial
anaemia in endemic regions of LA. The National Institutes of Health-National
Institute of Allergy and Infectious Diseases is currently funding the establishment
of the Centro Latino Americano de Investigación en Malaria (CLAIM) as
a Centre of Excellence for Malaria Research (ICEMR). The Centre aims, as a priority,
to determine the prevalence and severity of haematological manifestations attributable
to malaria infection and their association with concomitant immune status, including
nutritional factors and hel-minth coinfection. Although studies would initially
cover only Colombia, Panama, Peru and Guatemala, further expansion of malaria
research, including anaemia, would be extended to other countries of LA, to
the Caribbean region and Brazil. CLAIM already interacts with the Brazilian
Malaria Network, which aims to describe the determinants of P. vivax-related
severe anaemia in hospitalised patients from a tertiary care institution, specifically
focussing on the impacts of host genetics (G6PD deficiency and Fy genotypes)
and chloroquine resistance.
These multi-country
regional projects will allow the comparison of pathologies in settings with
different malaria transmission intensities in communities with great ethnic,
occupational and immune diversities. Moreover, the availability of the Aotus
monkey animal model in several countries of the LA region represents a valuable
resource to address important questions regarding malaria pathogenesis that
cannot be studied in the human populations. Indeed, the accessibility to BM
aspirates of non-human primates vaccinated with human malaria vaccine candidates
opens an interesting new area of research to complement the analyses of the
influences of specific antimalarial immune responses in the generation of anaemia.
ACKNOWLEDGEMENTS
To the participation
of endemic communities from malaria endemic areas of Colombia and Brazil, who
kindly accepted to participate in part of the studies mentioned here, and to
Paola Rojas, for her technical support to prepare this paper.
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