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Parasitology Research

, Volume 118, Issue 1, pp 377–382 | Cite as

Eryptosis of non-parasitized erythrocytes is related to anemia in Plasmodium berghei low parasitema malaria of Wistar rats

  • Paulo Renato Rivas TotinoEmail author
  • Hugo Amorim dos Santos de Souza
  • Edmar Henrique Costa Correa
  • Cláudio Tadeu Daniel-Ribeiro
  • Maria de Fátima Ferreira-da-Cruz
Immunology and Host-Parasite Interactions - Short Communication

Abstract

It is known that premature elimination of non-parasitized RBCs (nRBCs) plays an important role in the pathogenesis of malarial anemia, in which suicidal death process (eryptosis) of nRBCs has been suggested to be involved. To check this possibility, we investigate eryptosis during infection of P. berghei ANKA in Wistar rats, a malaria experimental model that, similar to human malaria, the infection courses with low parasitemia and acute anemia. As expected, P. berghei ANKA infection was marked by low parasite burdens that reached a mean peak of 3% between days six and nine post-infection and solved spontaneously. A significant reduction of the hemoglobin levels (~ 30%) was also observed on days subsequent to the peak of parasitemia, persisting until day 16 post-infection. In eryptosis assays, it was observed a significant increase in the levels of PS-exposing nRBC, which coincided with the reduction of hemoglobin levels and was positively related to anemia. In addition to PS externalization, eryptosis of nRBC induced by P. berghei infection was characterized by cytoplasm calcium influx, but not caspases activity. These results confirm our previous studies evidencing a pro-eryptotic effect of malaria infection on nRBCs and show that a caspase-independent eryptotic process is implicated in anemia induced by P. berghei ANKA infection in Wistar rats.

Keywords

Eryptosis P. berghei Malaria Anemia 

Notes

Funding information

This work received financial support from the Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ, Brazil) and Instituto Oswaldo Cruz (Fiocruz, Brazil). CTDR is recipient of a Research Productivity Fellowship from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) and CTDR and MFFC received grants from FAPERJ as “Cientistas do Nosso Estado”.

Compliance with ethical standards

All animal experiments were approved by the Ethical Committee of Animal Experiments of Instituto Oswaldo Cruz-Fiocruz (protocol: L-040/2015).

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. Al Mamun Bhuyan A, Bissinger R, Cao H, Lang F (2017) Triggering of suicidal erythrocyte death by exemestane. Cell Physiol Biochem 42:1–12.  https://doi.org/10.1159/000477224 CrossRefGoogle Scholar
  2. Berg CP, Engels IH, Rothbart A, Lauber K, Renz A, Schlosser SF, Schulze-Osthoff K, Wesselborg S (2001) Human mature red blood cells express caspase-3 and caspase-8, but are devoid of mitochondrial regulators of apoptosis. Cell Death Differ 8:1197–1206.  https://doi.org/10.1038/sj.cdd.4400905 CrossRefGoogle Scholar
  3. Bratosin D, Estaquier J, Petit F, Arnoult D, Quatannens B, Tissier JP, Slomianny C, Sartiaux C, Alonso C, Huart JJ, Montreuil J, Ameisen JC (2001) Programmed cell death in mature erythrocytes: a model for investigating death effector pathways operating in the absence of mitochondria. Cell Death Differ 8:1143–1156.  https://doi.org/10.1038/sj.cdd.4400946 CrossRefGoogle Scholar
  4. Chan WY, Lau PM, Yeung KW, Kong SK (2018) The second generation tyrosine kinase inhibitor dasatinib induced eryptosis in human erythrocytes - an in vitro study. Toxicol Lett 295:10–21.  https://doi.org/10.1016/j.toxlet.2018.05.030 CrossRefGoogle Scholar
  5. Chang HY, Yang X (2000) Proteases for cell suicide: functions and regulation of caspases. Microbiol Mol Biol Rev 64:821–846.  https://doi.org/10.1128/MMBR.64.4.821-846.2000 CrossRefGoogle Scholar
  6. Collins WE, Jeffery GM, Roberts JM (2003) A retrospective examination of anemia during infection of humans with Plasmodium vivax. Am J Trop Med Hyg 68:410–412.  https://doi.org/10.4269/ajtmh.2003.68.410 CrossRefGoogle Scholar
  7. Dondorp AM, Angus BJ, Chotivanich K, Silamut K, Ruangveerayuth R, Hardeman MR, Kager PA, Vreeken J, White NJ (1999) Red blood cell deformability as a predictor of anemia in severe falciparum malaria. Am J Trop Med Hyg 60:733–737.  https://doi.org/10.4269/ajtmh.1999.60.733 CrossRefGoogle Scholar
  8. Evans KJ, Hansen DS, van Rooijen N, Buckingham LA, Schofield L (2006) Severe malarial anemia of low parasite burden in rodent models results from accelerated clearance of uninfected erythrocytes. Blood 107:1192–1199.  https://doi.org/10.1182/blood-2005-08-3460 CrossRefGoogle Scholar
  9. Fendel R, Brandts C, Rudat A, Kreidenweiss A, Steur C, Appelmann I, Ruehe B, Schröder P, Berdel WE, Kremsner PG, Mordmüller B (2010) Hemolysis is associated with low reticulocyte production index and predicts blood transfusion in severe malarial anemia. PLoS One 5:e10038.  https://doi.org/10.1371/journal.pone.0010038 CrossRefGoogle Scholar
  10. Fernandez-Arias C, Rivera-Correa J, Gallego-Delgado J, Rudlaff R, Fernandez C, Roussel C, Götz A, Gonzalez S, Mohanty A, Mohanty S, Wassmer S, Buffet P, Ndour PA, Rodriguez A (2016) Anti-self phosphatidylserine antibodies recognize uninfected erythrocytes promoting malarial anemia. Cell Host Microbe 19:194–203.  https://doi.org/10.1016/j.chom.2016.01.009 CrossRefGoogle Scholar
  11. Gao M, Wong SY, Lau PM, Kong SK (2013) Ferutinin induces in vitro eryptosis/erythroptosis in human erythrocytes through membrane permeabilization and calcium influx. Chem Res Toxicol 26:1218–1228.  https://doi.org/10.1021/tx400127w CrossRefGoogle Scholar
  12. Gómez ND, Safeukui I, Adelani AA, Tewari R, Reddy JK, Rao S, Holder A, Buffet P, Mohandas N, Haldar K (2011) Deletion of a malaria invasion gene reduces death and anemia, in model hosts. PLoS One 6:e25477.  https://doi.org/10.1371/journal.pone.0025477 CrossRefGoogle Scholar
  13. Hedrich HJ (2000) History, strains and models. In: Krinke G (ed) The laboratory rat. Handbook of experimental animals. Academic Press, London, pp 3–7.  https://doi.org/10.1016/B978-012426400-7.50040-6 Google Scholar
  14. Helegbe GK, Goka BQ, Kurtzhals JA, Addae MM, Ollaga E, Tetteh JK, Dodoo D, Ofori MF, Obeng-Adjei G, Hirayama K, Awandare GA, Akanmori BD (2007) Complement activation in Ghanaian children with severe Plasmodium falciparum malaria. Malar J 6:165.  https://doi.org/10.1186/1475-2875-6-165 CrossRefGoogle Scholar
  15. Jakeman GN, Saul A, Hogarth WL, Collins WE (1999) Anaemia of acute malaria infections in non-immune patients primarily results from destruction of uninfected erythrocytes. Parasitology 119:127–133.  https://doi.org/10.1017/S0031182099004564 CrossRefGoogle Scholar
  16. Jemaà M, Fezai M, Bissinger R, Lang F (2017) Methods employed in cytofluorometric assessment of eryptosis, the suicidal erythrocyte death. Cell Physiol Biochem 43:431–444.  https://doi.org/10.1159/000480469 CrossRefGoogle Scholar
  17. Jilani K, Qadri SM, Lang E, Zelenak C, Rotte A, Bobbala D, Lang F (2011) Stimulation of erythrocyte phospholipid scrambling by enniatin A. Mol Nutr Food Res 55:S294–S302.  https://doi.org/10.1002/mnfr.201100156 CrossRefGoogle Scholar
  18. Kasinathan RS, Greenberg RM (2010) Schistosoma mansoni soluble egg antigens trigger erythrocyte cell death. Cell Physiol Biochem 26:767–774.  https://doi.org/10.1159/000322344 CrossRefGoogle Scholar
  19. Lamikanra AA, Brown D, Potocnik A, Casals-Pascual C, Langhorne J, Roberts DJ (2007) Malarial anemia: of mice and men. Blood 110:18–28.  https://doi.org/10.1182/blood-2006-09-018069 CrossRefGoogle Scholar
  20. Lang E, Lang F (2015) Triggers, inhibitors, mechanisms, and significance of eryptosis: the suicidal erythrocyte death. Biomed Res Int 2015:513518–513516.  https://doi.org/10.1155/2015/513518 CrossRefGoogle Scholar
  21. Lang F, Qadri SM (2012) Mechanisms and significance of eryptosis, the suicidal death of erythrocytes. Blood Purif 33:125–130.  https://doi.org/10.1159/000334163 CrossRefGoogle Scholar
  22. Lupescu A, Shaik N, Jilani K, Zelenak C, Lang E, Pasham V, Zbidah M, Plate A, Bitzer M, Föller M, Qadri SM, Lang F (2012) Enhanced erythrocyte membrane exposure of phosphatidylserine following sorafenib treatment: an in vivo and in vitro study. Cell Physiol Biochem 30:876–888.  https://doi.org/10.1159/000341465 CrossRefGoogle Scholar
  23. Munde EO, Raballah E, Okeyo WA, Ong'echa JM, Perkins DJ, Ouma C (2017) Haplotype of non-synonymous mutations within IL-23R is associated with susceptibility to severe malaria anemia in a P. falciparum holoendemic transmission area of Kenya. BMC Infect Dis 17:291.  https://doi.org/10.1186/s12879-017-2404-y CrossRefGoogle Scholar
  24. Okeyo WA, Munde EO, Okumu W, Raballah E, Anyona SB, Vulule JM, Ong'echa JM, Perkins DJ, Ouma C (2013) Interleukin (IL)-13 promoter polymorphisms (-7402 T/G and -4729G/A) condition susceptibility to pediatric severe malarial anemia but not circulating IL-13 levels. BMC Immunol 14:15.  https://doi.org/10.1186/1471-2172-14-15 CrossRefGoogle Scholar
  25. Qian EW, Ge DT, Kong SK (2012) Salidroside protects human erythrocytes against hydrogen peroxide-induced apoptosis. J Nat Prod 75:531–537.  https://doi.org/10.1021/np200555s CrossRefGoogle Scholar
  26. Safeukui I, Gomez ND, Adelani AA, Burte F, Afolabi NK, Akondy R, Velazquez P, Holder A, Tewari R, Buffet P, Brown BJ, Shokunbi WA, Olaleye D, Sodeinde O, Kazura J, Ahmed R, Mohandas N, Fernandez-Reyes D, Haldar K (2015) Malaria induces anemia through CD8+ T cell-dependent parasite clearance and erythrocyte removal in the spleen. MBio 6:e02493–e02414.  https://doi.org/10.1128/mBio.02493-14 CrossRefGoogle Scholar
  27. Stoute JA, Odindo AO, Owuor BO, Mibei EK, Opollo MO, Waitumbi JN (2003) Loss of red blood cell-complement regulatory proteins and increased levels of circulating immune complexes are associated with severe malarial anemia. J Infect Dis 187:522–525.  https://doi.org/10.1086/367712 CrossRefGoogle Scholar
  28. Totino PR, Magalhães AD, Silva LA, Banic DM, Daniel-Ribeiro CT, Ferreira-da-Cruz MF (2010) Apoptosis of non-parasitized red blood cells in malaria: a putative mechanism involved in the pathogenesis of anaemia. Malar J 9:350.  https://doi.org/10.1186/1475-2875-9-350 CrossRefGoogle Scholar
  29. Totino PR, Pinna RA, Oliveira AC, Banic DM, Daniel-Ribeiro CT, Ferreira-da-Cruz MF (2013) Apoptosis of non-parasitised red blood cells in Plasmodium yoelii malaria. Mem Inst Oswaldo Cruz 108:686–890.  https://doi.org/10.1590/0074-0276108062013003 CrossRefGoogle Scholar
  30. Totino PR, Daniel-Ribeiro CT, Ferreira-da-Cruz MF (2016) Evidencing the role of erythrocytic apoptosis in malarial anemia. Front Cell Infect Microbiol 6:176.  https://doi.org/10.3389/fcimb.2016.00176 CrossRefGoogle Scholar
  31. Varo R, Crowley VM, Sitoe A, Madrid L, Serghides L, Kain KC, Bassat Q (2018) Adjunctive therapy for severe malaria: a review and critical appraisal. Malar J 17:47.  https://doi.org/10.1186/s12936-018-2195-7 CrossRefGoogle Scholar
  32. Waitumbi JN, Opollo MO, Muga RO, Misore AO, Stoute JA (2000) Red cell surface changes and erythrophagocytosis in children with severe Plasmodium falciparum anemia. Blood 95:1481–1486Google Scholar
  33. World Health Organization (WHO) (2017) World Malaria Report 2017. WHO, GenevaCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Paulo Renato Rivas Totino
    • 1
    Email author
  • Hugo Amorim dos Santos de Souza
    • 1
  • Edmar Henrique Costa Correa
    • 1
  • Cláudio Tadeu Daniel-Ribeiro
    • 1
  • Maria de Fátima Ferreira-da-Cruz
    • 1
  1. 1.Laboratory for Malaria ResearchInstituto Oswaldo Cruz, Fundação Oswaldo CruzRio de JaneiroBrazil

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