Anemia is the primary clinical manifestation of malarial infections and is responsible for the substantial rate of morbidity. The pathophysiology discussed till now catalogued several causes for malarial anemia among which ineffective erythropoiesis being remarkable one occurs silently in the bone marrow. A systematic literature search was performed and summarized information on erythropoietic response upon malaria infection and the factors responsible for the same. This review summarizes the clinical and experimental studies on patients, mouse models, and in vitro cell cultures reporting erythropoietic changes upon malaria infection as well as factors accountable for the same. Inadequate erythropoietic response during malaria infection may be the collective effect of various mediators generated by host immune response as well as parasite metabolites. The interplay between various modulators causing the pathophysiology needs to be explored further. Globin gene expression profiling upon malaria infection should also be looked into as abnormal production of globin chains could be a possible contributor to ineffective erythropoiesis.
During malaria infection, anemia is a common complication and causes mortality and morbidity in patients, especially children and pregnant women [
The pathophysiology of malarial anemia is said to be complex and multifactorial [
During infection, there is obvious loss of infected erythrocytes through parasite maturation but many uninfected cells are also destroyed due to antibody sensitization or other physiochemical membrane changes and increased reticuloendothelial activity in spleen. Suppression of erythropoiesis has been said to be additional factor contributing to worsening the condition. Ineffective erythropoiesis (active erythropoiesis with premature death of red blood cells, a decreased output of erythrocytes from the bone marrow) and dyserythropoiesis (defective development of erythrocytes, such as anisocytosis and poikilocytosis) during malaria infection are profusely discussed topic and numerous clinical and experimental studies have been undertaken to demonstrate the same. Despite that, mechanism still remains unclear.
In this review, we summarized the four different approaches used by researchers to understand the erythropoiesis in malaria infections such as clinical evaluation of patients, in vivo mice studies, in vitro culture studies, and gene expression profiling as well as factors proposed or found to cause inappropriate erythropoietic response during infection.
A systematic literature search was performed and we summarized information on erythropoiesis on malaria infections and factors causing inadequate erythropoiesis. We searched for peer-reviewed articles published in English language in the PubMed and ScienceDirect databases.
We used search terms like malaria, erythropoiesis, ineffective erythropoiesis, dyserythropoiesis, and hemozoin in title, abstract, and keywords.
Total 1604 records were identified through database searches. Among those 1368 were excluded after reading titles, abstract, and keywords. Only peer-reviewed articles were included and conference abstracts, proceedings, and project reports were excluded. 255 full-text articles were assessed for the relevance to the subject of review and 76 were included in the main study.
A variety of abnormalities in the number, morphology, and function of blood and bone marrow cells were observed in human as well as murine
Decreased production of erythroid cells was almost always found to be associated with dyserythropoiesis, that is, the production of morphologically defective cells which in functional terms results in ineffective erythropoiesis [
The reticulocyte production index (RPI) is also used as marker in the diagnosis of anemia as well as in the determination of erythropoietic response. It is a standard measure of reticulocyte production that corrects for both the degree of anemia and the early release of reticulocytes from the bone marrow in anemic patients [
Similarly, in many studies, bone marrow inhibition was found to be correlated with the degree of parasitemia and could be reversed after clearance of parasites from blood. In the in vitro study of fifteen bone marrow cultures of
The above mentioned aspects of erythropoiesis were supported by the rodent malaria models which were proved to be useful in delineating the erythropoietic response followed by murine
Maggio-Price et al. [
In the recent years, after the successful production of erythrocytes from the in vitro cultures of haematopoietic stem cells [
Panichakul et al. [
Expression of CD71, essential for uptake of iron bound to transferrin, is normally increased on maturing erythroblasts that require iron from haemoglobin synthesis as well as on other actively growing cells [
Transcriptional changes can be utilized as an important first step in understanding the host cell’s adaptive response to infection by blood stage
Gene expression profiling of growing erythrocytes could be an important key for understanding the pathophysiology of the disease. During the intraerythrocytic phase of its life cycle, malaria parasite matures within a cell in which haemoglobin is the single major cytosolic protein. Haemoglobin is the main amino acid reservoir available to the intraerythrocytic
Imbalance in
Various host and parasite mediators responsible for the erythropoietic changes during malaria infection have been documented in the literature, hemozoin crystals and cytokines being largely discussed.
Hemozoin is a by-product of heme detoxification by malaria parasites through biocrystallization process. As the parasite multiplies in host, hemozoin is continuously produced and released together with the merozoites and engulfed by macrophages, monocytes, neutrophils, and other immune cells such as dendritic cells (DCs) [
Dysregulation in the innate immune response is believed to be an important cause of impaired erythroid responses in children with severe malarial anemia. The ability of
Dysregulation of innate inflammatory mediators is a result of phagocytosis of malarial pigment hemozoin by immune cells. During acute falciparum malaria in children, altered production of soluble immune mediators, such as nitric oxide (NO) and prostaglandin-E2 (PGE2), has been observed from peripheral blood mononuclear cells (PBMCs) [
Hemozoin has been shown to inhibit the erythroid development in vitro and in vivo. Hemozoin within the bone marrow and plasma levels of hemozoin in patients with malarial anemia were associated with reduced reticulocyte response [
After HZ/HNE treatment, expression of cell-cycle regulation proteins was investigated and the expressions of critical proteins, p53 and p21, were increased while the master transcription factor in erythropoiesis, GATA-1, was found to be reduced. The regulator protein of G1-to-S-phase transition (retinoblastoma protein) was consequently hypophosphorylated. HZ and HNE inhibited protein expression of crucial receptors (R) in erythropoiesis, namely, transferrin R1, stem cell factor R, interleukin-3R, and erythropoietin R. Thus it was clear that HZ and HNE inhibited erythropoiesis by interfering with cell cycle and cell-cycle regulation proteins acted as targets for HZ and HNE in the inhibition process.
Hemozoin leads to the continuous targeting of the host innate immune system, leading to both pro- and anti-inflammatory responses; thus, currently, the potential application of hemozoin crystals for their use in vaccine as an adjuvant has been evaluated [
Further studies may provide deeper insights into the molecular mechanisms involved in immune responses to malarial infection.
Severe disease in both human and mouse seems to be dependent on the levels of proinflammatory and anti-inflammatory cytokines. The relative balance between pro- and anti-inflammatory cytokines determines the degree of malarial anemia [
Parasites and its byproducts elevate a strong inflammatory response by increasing TNF
The potent anti-inflammatory cytokine, IL10, has been suggested as important factor to regulate TNF
In addition to cytokines, the important mediators in malaria pathogenesis are chemokines. Chemokines are chemotactic cytokines having the ability to induce directed chemotaxis in nearby responsive cells. Chemokines are important for bridging innate and adaptive immune responses and regulating hematopoietic maturation [
The chemokines expression profile has largely been studied for their potential role in regulating disease severity in malaria patients.
Ochiel et al. [
RANTES is a specific chemoattractant for memory T cells and regulates inflammation by promoting leukocyte activation, angiogenesis, antimicrobial effects, and hematopoiesis [
Ingestion of parasite infected erythrocytes or malarial pigment (hemozoin) induces the release of macrophage migration inhibitory factor (MIF) from macrophages, a proinflammatory mediator. MIF has been thought to have intrinsic role in the development of the anemic complications and bone marrow suppression that are associated with malaria infection. At concentrations found in the circulation of malaria infected patients, MIF was found to suppress erythropoietin-dependent erythroid colony formation. Moreover, MIF synergized with known antagonists of hematopoiesis, tumor necrosis factor, and
Mouse studies regarding MIF demonstrated similar observations. MIF was detected in the sera of
Consistent with the role of MIF as erythropoietic suppressor, the elevated serum MIF levels were found in patients with severe malaria [
Soluble factors of
These factors either individually or collectively generate an ineffective erythropoietic response. Understanding the interplay between these mediators would provide the insights into mechanism invoking inadequate erythropoiesis.
Inadequate erythropoiesis is the important pathophysiology of malarial anemia. Understanding the pathophysiology and associated host parasite interactions would provide deeper insights into immune mechanism involved in the malarial infection and would help in the development of therapeutic strategies to treat severe malarial anemia. The interplay between various modulators causing ineffective erythropoiesis needs to be explored further.
It is also important to check whether parasites or their products mount any transcriptional responses in globin genes and affect the balance among the globin chains that can be analyzed for their potential contribution to the ineffective erythropoiesis and dyserythropoiesis.
The authors declare that there is no conflict of interests regarding the publication of this paper.