Hostname: page-component-78c5997874-lj6df Total loading time: 0 Render date: 2024-11-16T01:20:37.832Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  09 May 2018

Daniela Boehm Open the ORCID record for Daniela Boehm [Opens in a new window] ,
Lydia Healy ,
Sarah Ring  and
Angus Bell Open the ORCID record for Angus Bell [Opens in a new window]
Daniela Boehm*
Affiliation:
Department of Microbiology, School of Genetics & Microbiology, Moyne Institute of Preventive Medicine, Trinity College Dublin, Dublin 2, Ireland
Lydia Healy
Affiliation:
Department of Microbiology, School of Genetics & Microbiology, Moyne Institute of Preventive Medicine, Trinity College Dublin, Dublin 2, Ireland
Sarah Ring
Affiliation:
Department of Microbiology, School of Genetics & Microbiology, Moyne Institute of Preventive Medicine, Trinity College Dublin, Dublin 2, Ireland
Angus Bell
Affiliation:
Department of Microbiology, School of Genetics & Microbiology, Moyne Institute of Preventive Medicine, Trinity College Dublin, Dublin 2, Ireland
*
Author for correspondence: Daniela Boehm, E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

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.

Keywords

Erythropoiesishaemozoinmalarial anaemiaPlasmodium falciparum
Type
Research Article
Information
Parasitology , Volume 145 , Issue 14 , December 2018 , pp. 1865 - 1875
Check for updates
Copyright
Copyright © Cambridge University Press 2018 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

*

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

References

Anstey, NM, et al. (2009) The pathophysiology of vivax malaria. Trends in Parasitology 25, 220–227.Google Scholar
Augustijn, KD, et al. (2007) Functional characterization of the Plasmodium falciparum and P. berghei homologues of macrophage migration inhibitory factor. Infection and Immunity 75, 1116–1128.Google Scholar
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, 155–162.Google Scholar
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, 5674–5682.Google Scholar
Bell, A and Boehm, D (2013) Anti-disease therapy for malaria – ‘resistance proof’? Current Pharmaceutical Design 19, 300–306.Google Scholar
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, 34–41.Google Scholar
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, 127–134.Google Scholar
Carney, C, et al. (2006) The basis of the immunomodulatory activity of malaria pigment (hemozoin). Journal of Biological Inorganic Chemistry 11, 917–929.Google Scholar
Casals-Pascual, C, et al. (2006) Suppression of erythropoiesis in malarial anemia is associated with hemozoin in vitro and in vivo. Blood 108, 2569–2577.Google Scholar
Casals-Pascual, C, et al. (2012) Hepcidin demonstrates a biphasic association with anemia in acute Plasmodium falciparum malaria. Haematologica 97, 1695–1698.Google Scholar
Castro-Gomes, T, et al. (2014) Potential immune mechanisms associated with anemia in Plasmodium vivax malaria: a puzzling question. Infection and Immunity 82, 3990–4000.Google Scholar
Clark, IA, et al. (2006) Human malarial disease: a consequence of inflammatory cytokine release. Malaria Journal 5, 85.Google Scholar
Coban, C, et al. (2010) The malarial metabolite hemozoin and its potential use as a vaccine adjuvant. Allergology International 59, 115–124.Google Scholar
Danis, K, et al. (2011) Autochthonous Plasmodium vivax malaria in Greece, 2011. Euro Surveillance 16, pii:19993.Google Scholar
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, 657–664.Google Scholar
Douglas, NM, et al. (2012) The anaemia of Plasmodium vivax malaria. Malaria Journal 11, 135.Google Scholar
Ebeling, W, et al. (1974) Proteinase K from Tritirachium album limber. European Journal of Biochemistry 47, 91–97.Google Scholar
Ekvall, H (2003) Malaria and anemia. Current Opinion in Hematology 10, 108–114.Google Scholar
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, 527–539.Google Scholar
Ghosh, K and Ghosh, K (2007) Pathogenesis of anemia in malaria: a concise review. Parasitology Research 101, 1463–1469.Google Scholar
Giarratana, MC, et al. (2005) Ex vivo generation of fully mature human red blood cells from hematopoietic stem cells. Nature Biotechnology 23, 69–74.Google Scholar
Giarratana, MC, et al. (2011) Proof of principle for transfusion of in vitro-generated red blood cells. Blood 118, 5071–5079.Google Scholar
Giribaldi, G, et al. (2004) Hemozoin- and 4-hydroxynonenal-mediated inhibition of erythropoiesis. Possible role in malarial dyserythropoiesis and anemia. Haematologica 89, 492–493.Google Scholar
Gonçalves, RM, et al. (2012) Cytokine balance in human malaria: does Plasmodium vivax elicit more inflammatory responses than Plasmodium falciparum? PLoS ONE 7, e44394.Google Scholar
Haldar, K and Mohandas, N (2009) Malaria, erythrocytic infection, and anemia. Hematology. American Society of Hematology. Education Program 2009, 87–93. doi: 2009/1/87 [pii]10.1182/asheducation-2009.1.87 [doi].Google Scholar
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.Google Scholar
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, 817–823.Google Scholar
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), 127–133.Google Scholar
Jaramillo, M, et al. (2009) Synthetic Plasmodium-like hemozoin activates the immune response: a morphology – function study. PLoS ONE 4, e6957.Google Scholar
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, 45–54.Google Scholar
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, 4868–4873.Google Scholar
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.Google Scholar
Lamikanra, AA, et al. (2009) Hemozoin (malarial pigment) directly promotes apoptosis of erythroid precursors. PLoS ONE 4, e8446.Google Scholar
Lamikanra, AA, et al. (2015) Distinct mechanisms of inadequate erythropoiesis induced by tumor necrosis factor alpha or malarial pigment. PLoS ONE 10, e0119836.Google Scholar
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, 1185–1196.Google Scholar
Miller, KL, et al. (1989) Tumor necrosis factor alpha and the anemia associated with murine malaria. Infection and Immunity 57, 1542–1546.Google Scholar
Murray, CJ, et al. (2012) Global malaria mortality between 1980 and 2010: a systematic analysis. The Lancet 379, 413–431.Google Scholar
Nweneka, CV, et al. (2010) Iron delocalisation in the pathogenesis of malarial anaemia. Transactions of the Royal Society of Tropical Medicine and Hygiene 104, 175–184.Google Scholar
Panichakul, T, et al. (2012) Suppression of erythroid development in vitro by Plasmodium vivax. Malaria Journal 11, 173.Google Scholar
Panichakul, T, et al. (2015) Plasmodium vivax inhibits erythroid cell growth through altered phosphorylation of the cytoskeletal protein ezrin. Malaria Journal 14, 138.Google Scholar
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, 1919–1924.Google Scholar
Pathak, VA and Ghosh, K (2016) Erythropoiesis in malaria infections and factors modifying the erythropoietic response. Anemia 2016, 8.Google Scholar
Perkins, DJ, et al. (2011) Severe malarial anemia: innate immunity and pathogenesis. International Journal of Biological Sciences 7, 1427–1442.Google Scholar
Poli, G, et al. (2008) 4-Hydroxynonenal: a membrane lipid oxidation product of medicinal interest. Medicinal Research Reviews 28, 569–631.Google Scholar
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, 100–108.Google Scholar
Schofield, L (2007) Rational approaches to developing an anti-disease vaccine against malaria. Microbes and Infection 9, 784–791.Google Scholar
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.Google Scholar
Schwarzer, E, et al. (2003) Malaria-parasitized erythrocytes and hemozoin nonenzymatically generate large amounts of hydroxy fatty acids that inhibit monocyte functions. Blood 101, 722–728.Google Scholar
Schwarzer, E, et al. (2008) Hemozoin and the human monocyte – a brief review of their interactions. Parassitologia 50, 143–145.Google Scholar
Shio, MT, et al. (2010) Innate inflammatory response to the malarial pigment hemozoin. Microbes and Infection 12, 889–899.Google Scholar
Skorokhod, OA, et al. (2010) Inhibition of erythropoiesis in malaria anemia: role of hemozoin and hemozoin-generated 4-hydroxynonenal. Blood 116, 4328–4337.Google Scholar
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, 140–149.Google Scholar
Wickramasinghe, SN, et al. (1987) The bone marrow in human cerebral malaria: parasite sequestration within sinusoids. British Journal of Haematology 66, 295–306.Google Scholar