Sickle Hemoglobin Confers Tolerance to Plasmodium Infection

Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Cell (Impact Factor: 33.12). 04/2011; 145(3):398-409. DOI: 10.1016/j.cell.2011.03.049
Source: PubMed

ABSTRACT Sickle human hemoglobin (Hb) confers a survival advantage to individuals living in endemic areas of malaria, the disease caused by Plasmodium infection. As demonstrated hereby, mice expressing sickle Hb do not succumb to experimental cerebral malaria (ECM). This protective effect is exerted irrespectively of parasite load, revealing that sickle Hb confers host tolerance to Plasmodium infection. Sickle Hb induces the expression of heme oxygenase-1 (HO-1) in hematopoietic cells, via a mechanism involving the transcription factor NF-E2-related factor 2 (Nrf2). Carbon monoxide (CO), a byproduct of heme catabolism by HO-1, prevents further accumulation of circulating free heme after Plasmodium infection, suppressing the pathogenesis of ECM. Moreover, sickle Hb inhibits activation and/or expansion of pathogenic CD8(+) T cells recognizing antigens expressed by Plasmodium, an immunoregulatory effect that does not involve Nrf2 and/or HO-1. Our findings provide insight into molecular mechanisms via which sickle Hb confers host tolerance to severe forms of malaria.

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Available from: Nuno Ribeiro Palha, Jul 15, 2014
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    • "In keeping with this notion, expression of stress-responsive genes that counter the deleterious effects of heme, e.g., the heme catabolizing enzyme HO- 1, provide tissue damage control and confer tolerance to malaria in mice (Ferreira et al., 2011; Pamplona et al., 2007; Seixas et al., 2009; Soares et al., 2009). The pathophysiologic relevance of this host protective response is supported by the finding that sickle trait, selected through human evolution based on its ability to confer protection against malaria, acts via activation of this stress-responsive pathway to confer disease tolerance to malaria (Ferreira et al., 2011; Rosenthal, 2011). Whether the protective effect of HO-1 impacts on the outcome of human malaria is not clear (Mendonç a et al., 2012; Sambo et al., 2010; Walther et al., 2012). "
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    ABSTRACT: Immune-driven resistance mechanisms are the prevailing host defense strategy against infection. By contrast, disease tolerance mechanisms limit disease severity by preventing tissue damage or ameliorating tissue function without interfering with pathogen load. We propose here that tissue damage control underlies many of the protective effects of disease tolerance. We explore the mechanisms of cellular adaptation that underlie tissue damage control in response to infection as well as sterile inflammation, integrating both stress and damage responses. Finally, we discuss the potential impact of targeting these mechanisms in the treatment of disease.
    Trends in Immunology 10/2014; 35(10). DOI:10.1016/ · 12.03 Impact Factor
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    • "The degree of protection conferred by the sickle phenomenon has been shown to correlate with intracellular HbS concentration implying a greater propensity to protection in homozygous subjects. The protective effect of the sickle haemoglobin on malaria has also been ascribed to aberrant host actin remodelling [37], and to accelerated breakdown of haem oxygenase, which is strongly induced by the sickle haemoglobin [38]. More recently, the role of dysregulated microRNA activity, where growth inhibitory host microRNAs are translocated into the parasite, or fuse with extant parasite mRNA transcripts to inhibit translation of enzymes critical for parasite development has also been described [39]. "
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    ABSTRACT: Sickle cell disease (SCD) is a genetic disorder common in malaria endemic areas. In endemic areas, malaria is a major cause of morbidity and mortality among SCD patients. This suggests the need for prompt initiation of efficacious anti-malarial therapy in SCD patients with acute malaria. However, there is no information to date, on the efficacy or safety of artemisinin combination therapy when used for malaria treatment in SCD patients. Children with SCD and acute uncomplicated malaria (n = 60) were randomized to treatment with artesunate-amodiaquine (AA), or artemether-lumefantrine (AL). A comparison group of non-SCD children (HbAA genotype; n = 59) with uncomplicated malaria were also randomized to treatment with AA or AL. Recruited children were followed up and selected investigations were done on days 1, 2, 3, 7, 14, 28, 35, and 42. Selected clinical and laboratory parameters of the SCD patients were also compared with a group of malaria-negative SCD children (n = 82) in steady state. The parasite densities on admission were significantly lower in the SCD group, compared with the non-SCD group (p = 0.0006). The parasite reduction ratio (PRR) was lower, clearance was slower (p < 0.0001), and time for initial parasitaemia to decline by 50 and 90% were longer for the SCD group. Adequate clinical and parasitological response (ACPR) on day 28 was 98.3% (58/59) in the SCD group and 100% (57/57) in the non-SCD group. Corresponding ACPR rates on day 42 were 96.5% (55/57) in the SCD group and 96.4% (53/55) in the non-SCD group. The fractional changes in haemoglobin, platelets and white blood cell counts between baseline (day 0) and endpoint (day 42) were 16.9, 40.6 and 92.3%, respectively, for the SCD group, and, 12.3, 48.8 and 7.5%, respectively, for the non-SCD group. There were no differences in these indices between AA- and AL-treated subjects. The parasite clearance of SCD children with uncomplicated malaria was slower compared with non-SCD children. AA and AL showed similar clinical and parasitological effects in the SCD and non-SCD groups. The alterations in WBC and platelet counts may have implications for SCD severity. Trial registration Current controlled trials ISRCTN96891086.
    Malaria Journal 09/2014; 13(1):369. DOI:10.1186/1475-2875-13-369 · 3.49 Impact Factor
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    • "This is achieved by suppressing the activity of Bach-1, transcriptional repressor of Hmox-1 gene (Sun et al., 2002; Gozzelino et al., 2010). The crucial role of HO-1 has already been demonstrated in cerebral and severe forms of malaria (Pamplona et al., 2007; Seixas et al., 2009; Ferreira et al., 2011); increased expression of this detoxifying enzyme strongly correlates with the ability to survive the infection. The protection afforded by HO-1 relies on the inhibition of heme sensitization to programmed cell death. "
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    ABSTRACT: Plasmodium infection during gestation may lead to severe clinical manifestations including abortion, stillbirth, intrauterine growth retardation, and low birth weight. Mechanisms underlying such poor pregnancy outcomes are still unclear. In the animal model of severe placental malaria (PM), in utero fetal death frequently occurs and mothers often succumb to infection before or immediately after delivery. Plasmodium berghei-infected erythrocytes (IEs) continuously accumulate in the placenta, where they are then phagocytosed by fetal-derived placental cells, namely trophoblasts. Inside the phagosomes, disruption of IEs leads to the release of non-hemoglobin bound heme, which is subsequently catabolized by heme oxygenase-1 into carbon monoxide, biliverdin, and labile iron. Fine-tuned regulatory mechanisms operate to maintain iron homeostasis, preventing the deleterious effect of iron-induced oxidative stress. Our preliminary results demonstrate that iron overload in trophoblasts of P. berghei-infected placenta is associated with fetal death. Placentas which supported normally developing embryos showed no iron accumulation within the trophoblasts. Placentas from dead fetuses showed massive iron accumulation, which was associated with parasitic burden. Here we present preliminary data suggesting that disruption of iron homeostasis in trophoblasts during the course of PM is a consequence of heme accumulation after intense IE engulfment. We propose that iron overload in placenta is a pathogenic component of PM, contributing to fetal death. The mechanism through which it operates still needs to be elucidated.
    Frontiers in Pharmacology 07/2014; 5:155. DOI:10.3389/fphar.2014.00155 · 3.80 Impact Factor
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