Refractoriness of Eryptotic Red Blood Cells to Plasmodium falciparum Infection: A Putative Host Defense Mechanism Limiting Parasitaemia

Totino, Paulo Renato Rivas; Daniel-Ribeiro, Cláudio Tadeu; Ferreira-da-Cruz, Maria de Fátima

doi:10.1371/journal.pone.0026575

Cited by 19 publications

(17 citation statements)

References 28 publications

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“…Eryptosis is triggered following infection with mycoplasma [28] or, as pointed out above, by the malaria pathogen Plasmodium [20,[29][30][31][32][33][34]. Intraerythrocytic plasmodia induce oxidative stress which in turn activates the Ca 2+ -permeable cation channels leading to Ca 2+ entry and eryptosis.…”

Section: Disclosure Statementmentioning

confidence: 99%

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Physiology and Pathophysiology of Eryptosis

Läng

Lang

Föller³

2012

Transfus Med Hemother

143

106

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Suicidal erythrocyte death (eryptosis) is characterized by cell shrinkage, cell membrane blebbing, and cell membrane phospholipid scrambling with phosphatidylserine exposure at the cell surface. Eryptotic cells adhere to the vascular wall and are rapidly cleared from circulating blood. Eryptosis is stimulated by an increase in cytosolic Ca²⁺ activity, ceramide, hyperosmotic shock, oxidative stress, energy depletion, hyperthermia, and a wide variety of xenobiotics and endogenous substances. Inhibitors of eryptosis include erythropoietin and nitric oxide. Enhanced eryptosis is observed in diabetes, renal insufficiency, hemolytic uremic syndrome, sepsis, mycoplasma infection, malaria, iron deficiency, sickle cell anemia, beta-thalassemia, glucose-6-phosphate dehydrogenase-(G6PD) deficiency, hereditary spherocytosis, paroxysmal nocturnal hemoglobinuria, Wilson’s disease, myelodysplastic syndrome, and phosphate depletion. Eryptosis is further enhanced in gene-targeted mice with deficient annexin 7, cGMP-dependent protein kinase type I (cGKI), AMP-activated protein kinase (AMPK), anion exchanger 1 (AE1), adenomatous polyposis coli (APC), and Klotho, as well as in mouse models of sickle cell anemia and thalassemia. Decreased eryptosis is observed in mice with deficient phosphoinositide-dependent kinase 1 (PDK1), platelet activating factor (PAF) receptor, transient receptor potential channel 6 (TRPC6), janus kinase 3 (JAK3), and taurine transporter (TAUT). Eryptosis may be a useful mechanism to remove defective erythrocytes prior to hemolysis. Excessive eryptosis may, however, compromise microcirculation and lead to anemia.

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Section: Disclosure Statementmentioning

confidence: 99%

“…Accordingly, eryptosis counteracts parasitemia. Thus, at least in mice, several eryptosis-inducing substances favorably influence the clinical course of the disease [3,29,30,32]. Moreover, genetic defects in humans and mice resulting in accelerated eryptosis may confer partial protection against a severe course of malaria [20].…”

Section: Disclosure Statementmentioning

confidence: 99%

Physiology and Pathophysiology of Eryptosis

Läng

Lang

Föller³

2012

Transfus Med Hemother

143

106

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“…Accordingly, phosphatidylserine exposing erythrocytes may impair microcirculation [35,107,110,111,112,113]. The proeryptotic effect of artesunate may be particularly strong in clinical disorders with accelerated eryptosis, such as sepsis [114], fever [115], malaria [103,104,116], sickle cell disease [117], thalassemia [118,119], Wilson's disease [120], iron deficiency [121] hepatic failure [122], malignancy [123], metabolic syndrome [124], diabetes [40,125], dehydration [70], renal insufficiency [126], hemolytic uremic syndrome [127], hyperphosphatemia [79] and phosphate depletion [128]. Under those conditions the use of artesunate may be contraindicated.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Suicidal Erythrocyte Death by Artesunate

Alzoubi

Calabrò

Bissinger

et al. 2014

Cell Physiol Biochem

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Background: The artemisinin derivative artesunate is effective in the treatment of severe malaria and is considered for the treatment of malignancy. Artesunate triggers tumor cell apoptosis, an effect at least in part mediated by mitochondria. Even though lacking mitochondria, erythrocytes may similarly enter suicidal death or eryptosis, which is characterized by cell shrinkage and breakdown of the phospholipid asymmetry of the cell membrane with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i), ceramide formation, and oxidative stress. The present study explored whether artesunate stimulates eryptosis. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, [Ca²⁺]_i from Fluo3-fluorescence, ceramide abundance from binding of specific antibodies, and oxidative stress from 2′,7′-dichlorodihydrofluorescein-diacetate fluorescence. Results: A 48 h exposure of human erythrocytes to artesunate significantly increased the percentage of annexin-V-binding cells (≥ 9 µg/ml) without significantly influencing forward scatter. Artesunate significantly increased [Ca²⁺]_i. The stimulation of annexin-V-binding by artesunate (15 µg/ml) was significantly blunted but not abolished by removal of extracellular Ca²⁺. Artesunate increased the ceramide abundance at the cell surface and the 2′,7′-dichlorodihydrofluorescein-diacetate fluorescence. Conclusions: Artesunate stimulates phosphatidylserine translocation at the erythrocyte cell membrane, an effect at least partially due to increase of [Ca²⁺]_i, stimulation of ceramide formation and generation of oxidative stress.

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“…2,[7][8][9] Intriguingly, many of these diseases are also associated with protection from severe malaria, 10,11 which has led some authors to propose a role for RBC senescence and clearance in malaria resistance. [12][13][14] RBC lifespan may be critically regulated by changes in intracellular adenosine nucleotide (adenosine triphosphate [ATP], adenosine 59-diphosphate [ADP], and adenosine 59-monophosphate [AMP]) levels. 15,16 For example, the shortened lifespan of RBCs in pyruvate kinase-deficient individuals and associated pathology has been linked to reduced RBC ATP levels.…”

Section: Introductionmentioning

confidence: 99%

Adenosine monophosphate deaminase 3 activation shortens erythrocyte half-life and provides malaria resistance in mice

Hortle

Nijagal

Bauer

et al. 2016

Blood

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Key Points• AMPD3 activation reduces red blood cell half-life, which is associated with increased oxidative stress and phosphatidylserine exposure.• AMPD3 activation causes malaria resistance through increased RBC turnover and increased RBC production.The factors that determine red blood cell (RBC) lifespan and the rate of RBC aging have not been fully elucidated. In several genetic conditions, including sickle cell disease, thalassemia, and G6PD deficiency, erythrocyte lifespan is significantly shortened. Many of these diseases are also associated with protection from severe malaria, suggesting a role for accelerated RBC senescence and clearance in malaria resistance. Here, we report a novel, N-ethyl-N-nitrosourea-induced mutation that causes a gain of function in adenosine 59-monophosphate deaminase (AMPD3). Mice carrying the mutation exhibit rapid RBC turnover, with increased erythropoiesis, dramatically shortened RBC lifespan, and signs of increased RBC senescence/eryptosis, suggesting a key role for AMPD3 in determining RBC half-life. Mice were also found to be resistant to infection with the rodent malaria Plasmodium chabaudi. We propose that resistance to P. chabaudi is mediated by increased RBC turnover and higher rates of erythropoiesis during infection. (Blood. 2016; 128(9):1290-1301) IntroductionThe lifespan of red blood cells (RBC) is tightly regulated, lasting some 120 days in humans and 51 days in mice. 1 Senescent RBCs are cleared from the bloodstream by macrophages of the reticuloendothelial system and are replaced with new erythrocytes.2-4 This destruction is not random, and it is highly dependent on RBC age. 4 The factors determining the rate of RBC aging, and thereby RBC lifespan, have not been fully elucidated.In several genetic conditions, including pyruvate kinase deficiency, sickle cell disease, thalassemia, hereditary spherocytosis, and G6PD deficiency, 5,6 erythrocyte lifespan is significantly shortened. In most cases, cells show signs of increased senescence, including increased oxidative stress and phosphatidylserine (PS) exposure.2,7-9 Intriguingly, many of these diseases are also associated with protection from severe malaria, 10,11 which has led some authors to propose a role for RBC senescence and clearance in malaria resistance. 15,16 For example, the shortened lifespan of RBCs in pyruvate kinase-deficient individuals and associated pathology has been linked to reduced RBC ATP levels. Similarly, ATP loss contributes to pathology in sickle cell disease.17 Erythrocytic ATP levels are controlled by adenosine monophosphate deaminase (AMPD3), which converts AMP to inosine 59-monophosphate (IMP) and plays an important role in maintaining the adenylate energy charge or the ratio of ATP to AMP. Thus, ATP loss may be mediated through AMPD3, which converts AMP to IMP. In most cells, the conversion of ITP back to AMP by adenylsuccinate synthetase and adenylsuccinate lyase balances AMPD3 activity. However, in RBCs, the machinery for conversion of IMP back to AMP is absent, and to maintain AM...

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Refractoriness of Eryptotic Red Blood Cells to Plasmodium falciparum Infection: A Putative Host Defense Mechanism Limiting Parasitaemia

Cited by 19 publications

References 28 publications

Physiology and Pathophysiology of Eryptosis

Physiology and Pathophysiology of Eryptosis

Stimulation of Suicidal Erythrocyte Death by Artesunate

Adenosine monophosphate deaminase 3 activation shortens erythrocyte half-life and provides malaria resistance in mice

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