The fate of such multiple iRBC is not known. StatementAll relevant data are within the paper. Abstract Malaria is usually a parasitic disease that causes severe hemolytic anemia in immunity and blood stage parasites. In order to understand the mechanism accounting for this resistance as well as the impact of hemin on eryptosis and plasma levels of scavenging hemopexin, reddish blood cells were labeled with biotin prior to hemin treatment and contamination. This strategy allowed discriminating hemin-treated from dgenerated reddish blood cells and to follow the contamination within these two populations of cells. Fluorescence microscopy analysis of biotinylated-red blood cells revealed increased reddish blood cells selectivity and a decreased permissibility of hemin-conditioned reddish blood cells for parasite invasion. These effects were also apparent in cultures using hemin-preconditioned human reddish blood cells. Interestingly, hemin did not alter the turnover of reddish blood cells nor their replenishment during contamination. Our results assign a function for hemin as a protective agent against high parasitemia, and suggest that the hemolytic nature of blood stage human malaria may be beneficial for the infected host. Introduction Malaria is usually a mosquito-borne infectious disease with a human etiology dating back to the divergence between great apes and humans, approximately 5 million years ago [1, 2]. This long period of interactions allowed both and humans to co-evolve in order to reach a trade-off state in which less than 1% of infected patients pass away [3]. However, considering the high number of afflicted individuals ( 200 000 000 per year), malaria remains one of the most fatal infectious disease of our era. requires the conversation with 2 cell types within the human body for completion of the complex life cycle, and the pathogenesis of malaria takes place during the asexual reproduction of the parasites in reddish blood cells (RBCs). The lasting coexistence of and humans has led to natural positive selection of numerous inherited blood disorders in malarial endemic areas that protect against malaria morbidity and mortality [4C8]. Among these are -thalassemia, sickle SMI-16a cell disease and glucose-6-phosphate dehydrogenase deficiency, which are pathologies of unique origins sharing several features that SMI-16a include weakened RBC membranes, anemia and hemolysis [6, 7, 9]. Hemolytic anemia is usually a hallmark of malaria, being the primary clinical manifestation of the contamination. The pathophysiology of malarial anemia is usually multifactorial and entails the lysis of RBCs concurrent to invasion and growth, decreased production of RBCs by the bone marrow and, to a greater extend, destruction of uninfected RBCs [10]. The prevalence of the latter contributes to the complexity of malarial anemia by preventing a possible correlation between parasite burden and the severity of RBC loss [11]. Numerous mechanisms have been proposed to explain the exacerbated removal of RBCs from blood circulation during malaria contamination, e.g. unspecific phagocytosis [11], accelerated RBCs senescence [12], opsonisation by auto-antibodies [13] and reduced membrane deformability [14]. Nonetheless, anemia, one of the most grievous manifestations of malaria, is still not fully defined and seems related to complex factors. In addition to the common symptoms of anemia (fatigue, dizziness, weakness), hemolysis also causes the release of hemoglobin (Hgb) into the blood circulation. In the presence of reactive oxygen species (ROS), Hgb gets rapidly oxidized into unstable methemoglobin that releases its heme groups, which, in turn, are oxidized to hemin (HE), a liposoluble, inflammatory and cytotoxic molecule [15, 16]. Previous studies have provided evidences that oxidative damage promotes HE-dependent eryptosis at very low HE concentrations (3C5 M) in the absence of the HE scavenger protein hemopexin [17, 18]. Many studies have expressed issues about the deleterious effects of HE in the pathogenesis of malaria [19, 20], especially since plasma hemopexin is known to be depleted in severe human malarial contamination [10, 21]. We have demonstrated a strong immune modulatory house of HE, manifested as decreased secretion of interleukin-12, sustained production of interleukin-10 by murine macrophages and blunted interferon- production by spleen cells [22, 23]. These effects are known to be related to enhanced parasitemia and inhibition of the crucial Th2 helper cells/Th1 sequential polarization required to promote protective immunity against malaria [24]. However, although we as well as others have exhibited how HE can possibly impair anti-malarial adaptive immunity, HE-preconditioned mice are guarded against high parasitemia when infected with blood-stage parasites [23]. The beneficial effect of HE on blood stage SMI-16a malaria may be concurrent to enhanced destruction of infected-RBCs (iRBCs) or to a reduced capacity for parasite invasion or differentiation in HE-treated RBCs. Considering the possible relationship between HE and the unexplained severity of malarial hemolytic anemia, as an inducer and/or as a naturally selected favorable KRIT1 result, it was of great.
