Figure 3. Prevalence of anaemia as affected by malaria parasite and fever status. Figure 4. Prevalence of anaemia as influenced by morbidity status. Table 2. Table 3. Table 4. Achidi, T. Apinjoh, J. Anchang-Kimbi, R. Mugri, A. Ngwai, and C. Ndong, M. Van Reenen, D. Boakye, W.
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Cardoso, C. Coimbra et al. Kotepui, B. SCF and Epo synergize to drive the proliferation of human erythroid progenitors and precursors , and induce anti-apoptotic activity. During erythroid precursor maturation an increase in expression of glycophorin A gpA in humans or Ter 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. 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.
This coincided with reduced reticulocytosis indicating functional disruption of RBC output from the bone marrow 59 , 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. Direct and indirect effects of parasite on the development of malarial anemia. 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.
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. 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 berghei 57 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.
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.
Many other proinflammatory cytokines such as IL, IL, and migration inhibitory factor MIF have also been implicated in the pathogenesis of anemia in malaria. IL is present at higher levels in nonlethal, compared with lethal, infections of P chabaudi , suggesting that this cytokine may be a stimulator of erythropoiesis.
The association of IL with severe falciparum malaria is less clear. In contrast, patients with acute disease and elevated levels of IL had marked increases in IL 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.
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 anti-inflammatory 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.
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. 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. A product discussed earlier, hemozoin, may also be more intimately linked to an innate immune response, and thus proinflammatory cytokine release, than previously thought. 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.
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. Intriguingly, induction of reticulocytosis by exogenous Epo prior to infection enhanced parasite multiplication and resulted in lethal infection. 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. 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.
The peptide hormone hepcidin has been implicated in mediating anemia of chronic disease or inflammation by reducing the availability of iron stores for erythropoiesis. 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 fold at peak parasitemia compared with that of naive animals. Lower rises in BFU-E 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.
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. 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.
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. 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 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. Contribution: A. Sign In or Create an Account. Sign In. Skip Nav Destination Content Menu.
Close Malaria in humans. Malaria in mice. Pathophysiology of malarial anemia. Article Navigation. Malarial anemia: of mice and men Abigail A. Lamikanra , Abigail A. This Site. Google Scholar. Douglas Brown , Douglas Brown. Alexandre Potocnik , Alexandre Potocnik. Jean Langhorne , Jean Langhorne.
David J. Roberts David J. Blood 1 : 18— Article history Submitted:. Cite Icon Cite. Figure 1. View large Download PPT.
Table 1 Key rodent malaria infections with features of anemia. Mouse strain. Features of infection. Features of anemia. Reference no. View Large. Table 2 Characteristics of disease during infection with P falciparum — and plasmodia-infecting mouse strains. Table 3 Pathological features of P falciparum and mouse malarial anemia. Figure 2. Figure 3. Conflict-of-interest disclosure: The authors declare no competing financial interests.
Search ADS. About 3. Young children and pregnant women are particularly vulnerable to the disease when they become infected. Malaria is preventable and curable, and increased efforts are dramatically reducing the malaria burden in many places.
Malaria is an acute febrile illness. Symptoms appear 7 days or more after the infective mosquito bite. The first symptoms; fever, headache, chills and vomiting may be mild. If not treated within 24 hours, P.
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