The Benign Allele
Published in Lab Times 04-2011.
Researchers from Oeiras, Portugal, discover how sickle hemoglobin protects against malaria.
Sickle cell anemia is an autosomal recessive genetic disorder characterized by rigid, sickle-shaped red blood cells (RBCs). The molecular defect is a point mutation in the gene encoding the beta-chain of hemoglobin, the oxygen-carrier in the blood. In the homozygotes, referred to as HbSS, abnormal RBCs produce severe complications including vasoconstriction, hemolysis and aplasia, all of which are lethal. The disease shows a high prevalence in tropical and sub-tropical regions viz. sub-Saharan Africa where malaria is endemic. Carriers (hemizygotes) of the sickle mutation, denoted HbS, do not develop the disease, but instead acquire a survival advantage against malaria. This elusive observation has instigated research over decades to identify the mechanism by which the sickle allele offers protection to Plasmodium infection. While conventional hypotheses suggest that sickle hemoglobin may reduce the titer of parasites that infect the host by merely getting in their way, Miguel Soares at the Instituto Gulbenkian de Ciencia, Portugal, believes that “sickle hemoglobin makes the host tolerant to the parasite”. His research team in Oeiras has recently dissected the molecular cascade elicited by a single sickle allele which eventually renders the host tolerant to severe forms of malaria (Cell, 145:398-409).
Heme-oxygenase 1 (HO-1) is a catabolic enzyme that breaks down heme into biliverdin, iron and carbon monoxide (CO). The protective role of HO-1 in several immune mediated inflammatory diseases, including experimental cerebral malaria (ECM), has been attributed to the release of CO which binds cell-free hemoglobin and prevents the release of cytotoxic heme. In their experiments, the Soares group could show that mice, hemizygous for sickle anemia and resistant to Plasmodium, had high levels of Hmox1 mRNA. Indeed, deleting even one Hmox1 allele in the hemizygotes resulted in ECM following a parasitic infection. HO-1 levels are in fact, induced by NF-E2-related factor 2 (Nrf2)-mediated transcriptional activation in these mutants. In addition, the group observed an HO-1 dependent decrease in the production of chemokines including CXCL10, notorious in the pathogenesis of ECM, in the mutant brain. This inhibition of chemokines may have a functional significance in the alleviating effect of sickle haemoglobin against ECM. Besides suppressing the accumulation of toxic free heme via the HO-1/CO pathway, the group also found that sickle hemoglobin inhibited overt expansion of pathogenic CD8+ T cells offering a ‘double-assurance’ in its protective role against ECM.
Their study implicates a general protective mechanism involving HO-1 in the acquisition of host-tolerance to Plasmodium infection and holds therapeutic prospects in the treatment of severe forms of malaria.
Photo: Blood cells by Jon McGovern via Creative Commons License