Apoptosis of non-parasitized red blood cells in malaria: a putative mechanism involved in the pathogenesis of anaemia

Abstract

BackgroundSevere anaemia is a common complication of Plasmodium falciparum malaria in hyperendemic regions. Premature elimination of non-parasitized red blood cells (nRBC) has been considered as one mechanism involved in the genesis of severe malaria anaemia. It has been reported that apoptosis can occur in RBC and, consequently, this cell death process could contribute to anaemia. This study was performed to evaluate the susceptibility of nRBC to apoptosis in a malaria anaemia murine model.MethodsBalb/c mice were intraperitonially inoculated with 1 × 106 P. yoelii 17XL parasitized RBC (pRBC) and, then, parasitaemia and anaemia were monitored. Apoptosis in both pRBC and nRBC was assessed during early and late phases of infection by flow cytometry using Syto 16 and annexin V-PE double staining and forward scatter measurement.ResultsAs expected, experimental infection of Balb/c mice with Plasmodium yoelii 17XL parasites was characterized by progressive increase of parasitaemia and acute anaemia, leading to death. Flow cytometry analysis showed that a number of pRBC was in the apoptotic process. It was noteworthy that the increase of nRBC apoptosis levels occurred in the late phase of infection, when anaemia degree was notably accentuated, while no significant alteration was observed in the early phase.ConclusionThe increased levels of nRBC apoptosis herein firstly reported, in malaria infection could represent a putative mechanism worsening the severity of malarial anaemia.

In Vivo Splenic Clearance Correlates with In Vitro Deformability of Red Blood Cells from Plasmodium yoelii-Infected Mice

“…Clinical studies have shown both similarities and differences in the malaria pathology in humans and mice in terms of invasion characteristics and malarial anemia (20). For the scope of our study, which concerned mainly mechanical RBC filtration in spleen, Plasmodium yoelii-infected mice were chosen as our mouse model for two reasons: first, mouse spleen trapping of Plasmodium yoelii-infected RBCs was demonstrated by prior experimental studies (40), and second, similar to Plasmodium falciparum infection in humans, where the massive destruction of uninfected RBCs plays a significant role in malarial anemia, nonparasitized RBCs in Plasmodium yoelii-infected mice are also believed to contribute to murine malarial anemia (41). Additionally, it should be noted that for a typical nonsinusal spleen, adhesion (rather than deformability) is believed to be the predominant mechanism for RBC removal, as the critical mesh size of the spleen is significantly larger.…”

Malaria-Related Anemia in Patients from Unstable Transmission Areas in Colombia

“…Although malaria parasites induce hemolysis as the result of parasite replication and subsequent rupture of the host red blood cells (RBCs), other mechanisms, such as dysregulation and/or suppression of erythropoiesis, as well as direct and indirect destruction of non-parasitized RBCs (nRBCs) have been described. 2,3 Increased levels of nRBC apoptosis, 18 accelerated senescence, 19 and accelerated destruction of nRBCs by either opsonization or complement activation [20][21][22] have also been documented as major inducers of malaria-related anemia. Additionally, micronutrient deficiencies, including iron, folate, and vitamin B12, are known to significantly contribute to malaria-related anemia.…”

Extracellular Methemoglobin Mediated Early ROS Spike Triggers Osmotic Fragility and RBC Destruction: An Insight into the Enhanced Hemolysis During Malaria

“…During malaria, accelerated RBC destruction attributes to induction of apoptosis like process in uninfected RBC and development of oxidative stress [5]. Oxidative stress developed during the first hour (a sharp ROS spike by 15 min) of MetHb treatment was found to be responsible for the observed loss of membrane fragility and hemolysis (Fig.…”

“…According to a rough estimate, during malaria every infected RBC (IRBC) causes lysis of ten or more uninfected RBC to exhibit hemolytic anemia [4]. A recent study correlates the enhanced uninfected RBC destruction through apoptosis with the observed development of anemia during malaria [5]. The mechanistic details of apoptosis in uninfected RBC or inducer molecules are not known but results indicate prooxidant molecules released from infected RBC might be responsible.…”

“…Besides direct oxidation of hemoglobin in cell free micro-environment, a number of extrinsic factors, such as, toxic drug molecules, metabolic by-products of pathogenic organisms, and pro-inflammatory cytokines cause imbalance of the oxidation/reduction system of RBC [6]. As a result, a large amount of intracellular hemoglobin oxidized to form methemoglobin and induce RBC cytoskeleton rearrangement, membrane depolarization, increase in deformity and hemolysis [5,9]. In most of the pathological situation, rate of RBC destruction is very high and underlying molecular events are not clear.…”