Numerous reports have shown that
P. vivax can be associated with severe anaemia [
2‐
12]. Haematologic profiles of pancytopaenia in blood and bone marrow [
16] and dyserythropoiesis in bone marrow [
15] have been reported in vivax malaria patients. However, the cause of reduction in blood cell production in the bone marrow of patients with vivax malaria is not completely understood. Anaemia in malaria is caused by excessive removal of non-parasitized erythrocytes, the immune destruction of parasite-infected red cells, as well as by the impaired compensation due to bone marrow dysfunction [
1,
15,
17,
26‐
28].
Plasmodium vivax requires reticulocytes for expansion of the blood stages [
29] and parasitaemia is generally low, therefore it is unlikely to be the primary cause of anaemia [
6]. This suggests that in addition to the simple destruction of infected red cells another mechanism is involved in anaemia in vivax malaria.
Recently, the production of erythrocytes from the
in vitro cultures of haematopoietic stem cells was achieved, as previously described [
23] and this model is now being applied to dissect the complexity of anaemia in malaria. The results presented in this study have revealed for the first time that
P. vivax can directly inhibited erythropoiesis, as shown by the reduction of erythroid growth in the presence of either lysed or intact IE. Erythroid progenitor cells were susceptible to the inhibitory effect of
P. vivax on cell expansion and this result is consistent with the previous report that young stages of erythroid cells were more susceptible to
P. vivax infection [
23]. The suppression of erythropoiesis in malarial anaemia is not unique to
P. vivax and has also been observed in infections from other
Plasmodium species
. In the complicated
Plasmodium falciparum infection, erythroid suppression is indicated by a decrease in the number of erythroid precursors as well as colony-forming units-erythroid (CFU-E) and burst-forming units-erythroid (BFU-E) in the bone marrow cultures [
30].
Plasmodium chabaudi can directly suppress the proliferation, differentiation and maturation of erythroid progenitor cells and causes inadequate reticulocytosis in mice [
31]. However, deficient erythropoietin production does not appear to be the cause of inadequate erythropoiesis in malaria [
32].
Decreased responsiveness of erythroid progenitor cells to erythropoietin as well as impaired erythropoietin production mediated by inflammatory cytokines has been reported to be involved in anaemia during inflammation [
33]. Consistent with this observation, TNF-a was reported to partly inhibit proliferation of erythroid progenitor cells in bone marrow cultures [
34]. Erythroid progenitor cells produced in this model were also susceptible to inhibition by exogenous TNF-a as shown in Figure
4a. However, endogenous TNF-a and IFN-g in erythroid cultures exposed to lysates or intact
P. vivax was undetectable (Figure
4b). This suggests that
P. vivax can also inhibit erythropoiesis independently of TNF-a and IFN-g. Inhibition of erythroid development that is independent of TNF-a and IFN-g has also been observed by exposure with
P. falciparum haemozoin [
35,
36]. However, other inflammatory cytokines may be involved and high levels of IL-10 were found to correlate positively with inhibition of proliferative peripheral blood mononuclear cells in the presence of
P. falciparum haemozoin [
37]. In this study, IL-10 was also detectable in supernatants from gECs in the presence of IEs and the role of this cytokine in the inhibition of erythropoiesis is currently being investigated. Interestingly,
P. vivax inhibited not only growth but also the differentiation of erythroid progenitor cells as shown by the reduction of glycophorin
+ and CD 71
+ cells and this is similar to the inhibitory effect of
P. falciparum haemozoin on erythroid cell development [
35,
38]. Moreover, vivax parasites were able to perturb the cell division but did not induce the cell death of erythroid progenitor cells. Defects in the cell cycle without apoptosis has also been observed with the inhibitory effect of
P. falciparum haemozoin on erythroid cell growth [
38]. It was found that
falciparum haemozoin-treated erythroid cells enhanced the expression of the transcription factor p53 and cdk-inhibitor p21 in addition the retinoblastoma protein, a central regulator of G- to S-phase transition was hypophosphorylated, while GATA-1, the master transcription factor in erythropoiesis was reduced [
38]. Therefore the molecular mechanisms underlying the suppression of erythropoiesis by
P. vivax or its products warrants further investigation. The findings of this study are consistent with the hypothesis that vivax parasites can suppress erythropoiesis. These results provide a better understanding of the role of chronic and persistent
P. vivax infection as a cause of anaemia. Prolonged exposure to vivax parasites can suppress erythropoiesis as well as inhibit reticulocyte production, which could prevent the restoration of the erythrocyte population in chronic parasitaemic
P. vivax infection. Many cases of patients with severe anaemia have been reported in vivax endemic areas in Thailand, Indonesian Papua, Korea, Pakistan, Venezuela, and Colombia [
3,
5,
7,
9,
10,
14]. These patients are often infected or re-infected with the vivax parasites and parasites have the potential to inhibit erythroid development leading to ineffective erythropoiesis causing severe anaemia.