Article

Sickle Hemoglobin Confers Tolerance to Plasmodium Infection

Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Cell (Impact Factor: 32.24). 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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    • "A better understanding of the miR-451 role in Pf-iE came from a study using sickle cell (HbS) erythrocytes. In the context of malaria, a well-established resistance to infection is associated with this specific cell type (Cholera et al., 2008; Cyrklaff et al., 2011; Ferreira et al., 2011). Recently, La Monte and colleagues found a role for miRNAs from HbS erythrocytes in resistance against malaria (Lamonte et al., 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: MicroRNAs (miRNAs), a class of small non-coding regulatory RNAs, have been detected in a variety of organisms ranging from ancient unicellular eukaryotes to mammals. They have been associated with numerous molecular mechanisms involving developmental, physiological and pathological changes of cells and tissues. Despite the fact that miRNA-silencing mechanisms appear to be absent in some Apicomplexan species, an increasing number of studies have reported a role for miRNAs in host-parasite interactions. Host miRNA expression can change following parasite infection and the consequences can lead, for instance, to parasite clearance. In this context, the immune system signaling appears to have a crucial role.
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    • "Because of their variant hemoglobin, sickle cells release more heme into the plasma than do normal erythrocytes, which, in turn, stimulates the synthesis of hemoxygenase I by hematopoietic cells. Hemoxygenase I catalyzes the breakdown of heme, resulting in the production of the gasotransmitter carbon monoxide, which is thought to modulate the malaria-induced disease-mediating inflammatory reactions in the brain and other vital organs (Ferreira et al., 2011). Recent evidence has pointed towards a role of hemoglobinopathies in interfering with cytoadhesion. "
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    Full-text · Article · Feb 2015 · Biology Open
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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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