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Inhibition of ex vivo erythropoiesis by secreted and haemozoin-associated Plasmodium falciparum products

  • Daniela Boehm (a1), Lydia Healy (a1), Sarah Ring (a1) and Angus Bell (a1)


It has been estimated that up to a third of global malaria deaths may be attributable to malarial anaemia, with children and pregnant women being those most severely affected. An inefficient erythropoietic response to the destruction of both infected and uninfected erythrocytes in infections with Plasmodium spp. contributes significantly to the development and persistence of such anaemia. The underlying mechanisms, which could involve both direct inhibition of erythropoiesis by parasite-derived factors and indirect inhibition as a result of modulation of the immune response, remain poorly understood. We found parasite-derived factors in conditioned medium (CM) of blood-stage Plasmodium falciparum and crude isolates of parasite haemozoin directly to inhibit erythropoiesis in an ex vivo model based on peripheral blood haematopoietic stem cells. Erythropoiesis-inhibiting activity was detected in a fraction of CM that was sensitive to heat inactivation and protease digestion. Erythropoiesis was also inhibited by crude parasite haemozoin but not by detergent-treated, heat-inactivated or protease-digested haemozoin. These results suggest that the erythropoiesis-inhibiting activity in both cases is mediated by proteins or protein-containing biomolecules and may offer new leads to the treatment of malarial anaemia.


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Author for correspondence: Daniela Boehm, E-mail:


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Present address: Daniela Boehm, School of Food Science and Environmental Health, Dublin Institute of Technology, Dublin 1, Ireland.



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Anstey, NM, et al. (2009) The pathophysiology of vivax malaria. Trends in Parasitology 25, 220227.
Augustijn, KD, et al. (2007) Functional characterization of the Plasmodium falciparum and P. berghei homologues of macrophage migration inhibitory factor. Infection and Immunity 75, 11161128.
Awandare, GA, et al. (2011) Mechanisms of erythropoiesis inhibition by malarial pigment and malaria-induced proinflammatory mediators in an in vitro model. American Journal of Hematology 86, 155162.
Barrera, V, et al. (2011) Host fibrinogen stably bound to hemozoin rapidly activates monocytes via TLR-4 and CD11b/CD18-integrin: a new paradigm of hemozoin action. Blood 117, 56745682.
Bell, A and Boehm, D (2013) Anti-disease therapy for malaria – ‘resistance proof’? Current Pharmaceutical Design 19, 300306.
Boehm, D and Bell, A (2014) Simply red: a novel spectrophotometric erythroid proliferation assay as a tool for erythropoiesis and erythrotoxicity studies. Biotechnology Reports 4, 3441.
Boehm, D, Murphy, WG and Al-Rubeai, M (2009) The potential of human peripheral blood derived CD34 + cells for ex vivo red blood cell production. Journal of Biotechnology 144, 127134.
Carney, C, et al. (2006) The basis of the immunomodulatory activity of malaria pigment (hemozoin). Journal of Biological Inorganic Chemistry 11, 917929.
Casals-Pascual, C, et al. (2006) Suppression of erythropoiesis in malarial anemia is associated with hemozoin in vitro and in vivo. Blood 108, 25692577.
Casals-Pascual, C, et al. (2012) Hepcidin demonstrates a biphasic association with anemia in acute Plasmodium falciparum malaria. Haematologica 97, 16951698.
Castro-Gomes, T, et al. (2014) Potential immune mechanisms associated with anemia in Plasmodium vivax malaria: a puzzling question. Infection and Immunity 82, 39904000.
Clark, IA, et al. (2006) Human malarial disease: a consequence of inflammatory cytokine release. Malaria Journal 5, 85.
Coban, C, et al. (2010) The malarial metabolite hemozoin and its potential use as a vaccine adjuvant. Allergology International 59, 115124.
Danis, K, et al. (2011) Autochthonous Plasmodium vivax malaria in Greece, 2011. Euro Surveillance 16, pii:19993.
de Mast, Q, et al. (2009) Mild increases in serum hepcidin and interleukin-6 concentrations impair iron incorporation in haemoglobin during an experimental human malaria infection. British Journal of Haematology 145, 657664.
Douglas, NM, et al. (2012) The anaemia of Plasmodium vivax malaria. Malaria Journal 11, 135.
Ebeling, W, et al. (1974) Proteinase K from Tritirachium album limber. European Journal of Biochemistry 47, 9197.
Ekvall, H (2003) Malaria and anemia. Current Opinion in Hematology 10, 108114.
Fennell, BJ, Al-shatr, ZA and Bell, A (2008) Isotype expression, post-translational modification and stage-dependent production of tubulins in erythrocytic Plasmodium falciparum. International Journal for Parasitology 38, 527539.
Ghosh, K and Ghosh, K (2007) Pathogenesis of anemia in malaria: a concise review. Parasitology Research 101, 14631469.
Giarratana, MC, et al. (2005) Ex vivo generation of fully mature human red blood cells from hematopoietic stem cells. Nature Biotechnology 23, 6974.
Giarratana, MC, et al. (2011) Proof of principle for transfusion of in vitro-generated red blood cells. Blood 118, 50715079.
Giribaldi, G, et al. (2004) Hemozoin- and 4-hydroxynonenal-mediated inhibition of erythropoiesis. Possible role in malarial dyserythropoiesis and anemia. Haematologica 89, 492493.
Gonçalves, RM, et al. (2012) Cytokine balance in human malaria: does Plasmodium vivax elicit more inflammatory responses than Plasmodium falciparum? PLoS ONE 7, e44394.
Haldar, K and Mohandas, N (2009) Malaria, erythrocytic infection, and anemia. Hematology. American Society of Hematology. Education Program 2009, 8793. doi: 2009/1/87 [pii]10.1182/asheducation-2009.1.87 [doi].
Helleberg, M, et al. (2005) Bone marrow suppression and severe anaemia associated with persistent Plasmodium falciparum infection in African children with microscopically undetectable parasitaemia. Malaria Journal 4, 56.
Hemmer, CJ, et al. (2006) Stronger host response per parasitized erythrocyte in Plasmodium vivax or ovale than in Plasmodium falciparum malaria. Tropical Medicine & International Health 11, 817823.
Jakeman, GN, et al. (1999) Anaemia of acute malaria infections in non-immune patients primarily results from destruction of uninfected erythrocytes. Parasitology 119 (Pt 2), 127133.
Jaramillo, M, et al. (2009) Synthetic Plasmodium-like hemozoin activates the immune response: a morphology – function study. PLoS ONE 4, e6957.
Keller, CC, et al. (2004 a) Reduced peripheral PGE2 biosynthesis in Plasmodium falciparum malaria occurs through hemozoin-induced suppression of blood mononuclear cell cyclooxygenase-2 gene expression via an interleukin-10-independent mechanism. Molecular Medicine 10, 4554.
Keller, CC, et al. (2004 b) Elevated nitric oxide production in children with malarial anemia: hemozoin-induced nitric oxide synthase type 2 transcripts and nitric oxide in blood mononuclear cells. Infection and Immunity 72, 48684873.
Kinung'hi, SM, et al. (2014) Malaria and helminth co-infections in school and preschool children: a cross-sectional study in Magu district, north-western Tanzania. PLoS ONE 9, e86510.
Lamikanra, AA, et al. (2009) Hemozoin (malarial pigment) directly promotes apoptosis of erythroid precursors. PLoS ONE 4, e8446.
Lamikanra, AA, et al. (2015) Distinct mechanisms of inadequate erythropoiesis induced by tumor necrosis factor alpha or malarial pigment. PLoS ONE 10, e0119836.
McDevitt, MA, et al. (2006) A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia. Journal of Experimental Medicine 203, 11851196.
Miller, KL, et al. (1989) Tumor necrosis factor alpha and the anemia associated with murine malaria. Infection and Immunity 57, 15421546.
Murray, CJ, et al. (2012) Global malaria mortality between 1980 and 2010: a systematic analysis. The Lancet 379, 413431.
Nweneka, CV, et al. (2010) Iron delocalisation in the pathogenesis of malarial anaemia. Transactions of the Royal Society of Tropical Medicine and Hygiene 104, 175184.
Panichakul, T, et al. (2012) Suppression of erythroid development in vitro by Plasmodium vivax. Malaria Journal 11, 173.
Panichakul, T, et al. (2015) Plasmodium vivax inhibits erythroid cell growth through altered phosphorylation of the cytoskeletal protein ezrin. Malaria Journal 14, 138.
Parroche, P, et al. (2007) Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9. Proceedings of the National Academy of Sciences of the United States of America 104, 19191924.
Pathak, VA and Ghosh, K (2016) Erythropoiesis in malaria infections and factors modifying the erythropoietic response. Anemia 2016, 8.
Perkins, DJ, et al. (2011) Severe malarial anemia: innate immunity and pathogenesis. International Journal of Biological Sciences 7, 14271442.
Poli, G, et al. (2008) 4-Hydroxynonenal: a membrane lipid oxidation product of medicinal interest. Medicinal Research Reviews 28, 569631.
Pradhan, P (2009) Malarial anaemia and nitric oxide induced megaloblastic anaemia: a review on the causes of malarial anaemia. Journal of Vector Borne Diseases 46, 100108.
Schofield, L (2007) Rational approaches to developing an anti-disease vaccine against malaria. Microbes and Infection 9, 784791.
Schwarzer, E, Arese, P and Skorokhod, OA (2015) Role of the lipoperoxidation product 4-hydroxynonenal in the pathogenesis of severe malaria anemia and malaria immunodepression. Oxidative Medicine and Cellular Longevity 2015, 638416.
Schwarzer, E, et al. (2003) Malaria-parasitized erythrocytes and hemozoin nonenzymatically generate large amounts of hydroxy fatty acids that inhibit monocyte functions. Blood 101, 722728.
Schwarzer, E, et al. (2008) Hemozoin and the human monocyte – a brief review of their interactions. Parassitologia 50, 143145.
Shio, MT, et al. (2010) Innate inflammatory response to the malarial pigment hemozoin. Microbes and Infection 12, 889899.
Skorokhod, OA, et al. (2010) Inhibition of erythropoiesis in malaria anemia: role of hemozoin and hemozoin-generated 4-hydroxynonenal. Blood 116, 43284337.
Thawani, N, et al. (2014) Plasmodium products contribute to severe malarial anemia by inhibiting erythropoietin-induced proliferation of erythroid precursors. Journal of Infectious Diseases 209, 140149.
Wickramasinghe, SN, et al. (1987) The bone marrow in human cerebral malaria: parasite sequestration within sinusoids. British Journal of Haematology 66, 295306.



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