Suicide for Survival - Death of Infected Erythrocytes as a Host Mechanism to Survive Malaria

Abstract

The pathogen of malaria, Plasmodium, enters erythrocytes and thus escapes recognition by the immune system. The pathogen induces oxidative stress to the host erythrocyte, which triggers eryptosis, the suicidal death of erythrocytes. Eryptosis is characterized by cell shrinkage, membrane blebbing and cell membrane phospholipid scrambling with phosphatidylserine exposure at the cell surface. Phosphatidylserine-exposing erythrocytes are identified by macrophages which engulf and degrade the eryptotic cells. To the extent that infected erythrocytes undergo eryptosis prior to exit of Plasmodiaand subsequent infection of other erythrocytes, the premature eryptosis may protect against malaria. Accordingly, any therapeutical intervention accelerating suicidal death of infected erythrocytes has the potential to foster elimination of infected erythrocytes, delay the development of parasitemia and favorably influence the course of malaria. Eryptosis is stimulated by a wide variety of triggers including osmotic shock, oxidative stress, energy depletion and a wide variety of xenobiotics. Diseases associated with accelerated eryptosis include sepsis, haemolytic uremic syndrome, malaria, sickle-cell anemia, beta-thalassemia, glucose-6-phosphate dehydrogenase (G6PD)-deficiency, phosphate depletion, iron deficiency and Wilson’s disease. Among the known stimulators of eryptosis, paclitaxel, chlorpromazine, cyclosporine, curcumin, PGE₂ and lead have indeed been shown to favourably influence the course of malaria. Moreover, sickle-cell trait, beta-thalassemia trait, glucose-6-phosphate dehydrogenase (G6PD)-deficiency and iron deficiency confer some protection against a severe course of malaria. Importantly, counteracting Plasmodia by inducing eryptosis is not expected to generate resistance of the pathogen, as the proteins involved in suicidal death of the host cell are not encoded by the pathogen and thus cannot be modified by mutations of its genes.

Stimulation of Suicidal Erythrocyte Death by Sulforaphane

“…On the one hand, eryptosis accomplishes the elimination of defective erythrocytes and thus protects against untoward effects of haemolysis [11]. Moreover, the removal of phosphatidylserine-exposing erythrocytes may counteract parasitaemia in malaria [70]. Intraerythrocytic parasites activate ion channels including the Ca 2 + -permeable erythrocyte cation channels [92,93] thus leading to Ca 2+ entry and subsequent eryptosis, which is followed by rapid clearance of the infected erythrocytes from circulating blood [70].…”

“…Moreover, the removal of phosphatidylserine-exposing erythrocytes may counteract parasitaemia in malaria [70]. Intraerythrocytic parasites activate ion channels including the Ca 2 + -permeable erythrocyte cation channels [92,93] thus leading to Ca 2+ entry and subsequent eryptosis, which is followed by rapid clearance of the infected erythrocytes from circulating blood [70]. Genetic disorders sensitizing erythrocytes to eryptosis, such as sickle cell trait, b-thalassaemia trait, homozygous Hb-C and G6PD deficiency [11], lead to a relatively mild clinical course of malaria [11,75,94,95].…”

“…Eryptosis is elicited by a wide variety of xenobiotics [13,, including tannic acid [48], honokiol [62], gossypol [46], gambogic acid [63], tanshinone II A [47], apigenin [64], ursolic acid [65], thymoquinone [66], oridonin [67] and a-lipoic acid [14]. Moreover, eryptosis is accelerated in a wide variety of clinical conditions [11,68], including sepsis [69], fever [16], malaria [29,[70][71][72][73], sickle cell disease [43,[74][75][76][77][78][79][80], Wilson's disease [81], iron deficiency [82], malignancy [83], metabolic syndrome [44], diabetes [30], renal insufficiency [39,84,85], haemolytic uremic syndrome [86], hyperphosphataemia [87] and phosphate depletion [68].…”

Roles of the NFκB and glutathione pathways in mature human erythrocytes

“…1). PS exposure and cell shrinkage are the hallmarks of eryptosis, the suicidal death of erythrocytes [14][15][16]. In control experiments, we excluded a non-specific lytic effect of the NFκB inhibitors at the concentrations used [6].…”

Proteomic mining of the red blood cell: focus on the membrane proteome

“…But remarkably, the parasites stay one step ahead of the immune system by presenting extreme diversity in PfEMP1 isoforms: there are over 60 variations of the protein within a single parasite and virtually limitless versions within parasite populations [39]. Furthermore, there are other RBC proteins of particular interest, such as glucose-6-phosphate dehydro genase or Duffy antigens (used by Plasmodium vivax to enter the cell), whose expression deficiency in RBCs results in increased protection against P. vivax Editorial Proteomic mining of the red blood cell: focus on the membrane proteome and severe malaria [40][41][42]. These facts alone present major challenges for clinicians and researchers, and set important cases for the continued detailed study of the RBC membrane proteome.…”