Oxidative insult can induce malaria-protective trait of sickle and fetal erythrocytes

Cyrklaff, Marek; Srismith, Sirikamol; Nyboer, Britta; Burda, Květoslava; Hoffmann, Angelika; Lasitschka, Felix; Adjalley, Sophie H.; Bisseyé, Cyrille; Simporé, Jacques; Mueller, Ann‐Kristin; Sánchez, Cecilia P.; Frischknecht, Friedrich; Lanzer, Michael

doi:10.1038/ncomms13401

Cited by 50 publications

(66 citation statements)

References 74 publications

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“…Some studies have observed that parasites can grow normally in AS RBCs at 3% and 5% O 2 (19,(38)(39)(40). This may be due to technical differences in culture format and growth assessments.…”

Section: Discussionmentioning

confidence: 99%

Resistance to Plasmodium falciparum in sickle cell trait erythrocytes is driven by oxygen-dependent growth inhibition

Archer

Petersen

Clark

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

112

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Sickle cell trait (AS) confers partial protection against lethal malaria. Multiple mechanisms for this have been proposed, with a recent focus on aberrant cytoadherence of parasite-infected red blood cells (RBCs). Here we investigate the mechanistic basis of AS protection through detailed temporal mapping. We find that parasites in AS RBCs maintained at low oxygen concentrations stall at a specific stage in the middle of intracellular growth before DNA replication. We demonstrate that polymerization of sickle hemoglobin (HbS) is responsible for this growth arrest of intraerythrocytic parasites, with normal hemoglobin digestion and growth restored in the presence of carbon monoxide, a gaseous antisickling agent. Modeling of growth inhibition and sequestration revealed that HbS polymerization-induced growth inhibition following cytoadherence is the critical driver of the reduced parasite densities observed in malaria infections of individuals with AS. We conclude that the protective effect of AS derives largely from effective sequestration of infected RBCs into the hypoxic microcirculation.

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Section: Discussionmentioning

confidence: 99%

Resistance to Plasmodium falciparum in sickle cell trait erythrocytes is driven by oxygen-dependent growth inhibition

Archer

Petersen

Clark

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

112

View full text Add to dashboard Cite

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“…These two hemoglobin variants have been associated with protection against severe malaria syndromes in numerous epidemiological studies 4 , and mechanistic hypotheses proposed to explain this protection include impaired blood stage parasite development 5 – 7 , reduced cytoadherence of infected red blood cells 8 , 9 , which is linked to the redox imbalance of hemoglobinopathies and its effects on the export of parasite-encoded proteins 10 , 11 , tolerance to malaria infection related to heme catabolism by heme oxygenase-1 12 , or accelerated acquisition of immunity 13 – 15 . Life-threatening episodes, however, represent only a small proportion of falciparum infections 16 , including in susceptible individuals 1 , and these same mechanisms might regulate other epidemiologically important parameters in non-severe infections, such as duration of parasite carriage and infectiousness.…”

Section: Introductionmentioning

confidence: 99%

Hemoglobin variants shape the distribution of malaria parasites in human populations and their transmission potential

Gonçalves

Sagara

Coulibaly

et al. 2017

Sci Rep

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Hemoglobin variants C and S protect against severe malaria but their influence on parameters not directly linked to disease severity such as gametocyte carriage and infection chronicity is less well understood. To assess whether these infection-related phenotypes depend on the host hemoglobin genotype, we followed 500 Malian individuals over 1–2 years and determined their parasitological status during monthly visits and incidental clinical episodes. While adults heterozygous for hemoglobin S mutation were less often parasitemic compared to AA adults (odds ratio [OR] 0.50 95% confidence interval [CI] 0.31–0.79, P = 0.003), schoolchildren (but not toddlers or adults) with AC genotype carried parasites, including gametocytes, more often than their AA counterparts (OR 3.01 95% CI 1.38–6.57, P = 0.006). AC children were also likelier to be parasite-positive during the dry season, suggesting longer infections, and were more infectious in mosquito skin feeding assays than AA children. Notably, AC school-aged children, who comprise ~5% of the population, harbor a third of infections with patent gametocytes between May and August, when transmission transitions from very low to intense. These findings indicate that schoolchildren with hemoglobin C mutation might contribute disproportionately to the seasonal malaria resurgence in parts of West Africa where the HbC variant is common.

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“…In support of this latter hypothesis, two recently-published studies have shown that in static adhesion assays, VAR2CSA-expressing FCR3 parasites in HbAS and HbAC erythrocytes exhibit significant reductions in adherence to CSA compared to those grown in HbAA erythrocytes, this decreased binding being much greater for parasitized HbAC than HbAS erythrocytes 26, 27 . However, these studies assessed only a single parasite strain in static but not flow adhesion assays.…”

Section: Discussionmentioning

confidence: 76%

Heterozygous HbAC but not HbAS is associated with higher newborn birthweight among women with pregnancy-associated malaria

Tétard

Milet

Dechavanne

et al. 2017

Sci Rep

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Pregnancy-associated malaria (PAM) is associated with poor pregnancy outcomes. Hemoglobin S (HbS) and hemoglobin C (HbC) mutations are frequently encountered in malaria-endemic areas of Africa, where they protect children from severe and uncomplicated Plasmodium falciparum malaria. However, scant epidemiological data exist on the impact of these Hb variants on PAM. A prospective cohort of 635 Beninese pregnant women was recruited before 24 weeks of gestational age and followed until the end of pregnancy. HbAA, HbAC, and HbAS genotypes were determined and tested for association with pregnancy outcomes and PAM indicators using linear and logistic multivariate models. Newborns from HbAC mothers had higher birthweights than those from HbAA mothers among women infected at any time during pregnancy (mean difference 182.9 g, p = 0.08), or during the first half of pregnancy (654.3 g, p = 0.0006). No such birthweight differences were observed between newborns from HbAS and HbAA mothers. HbAC and HbAS were not associated with other pregnancy outcomes or PAM indicators. In conclusion, HbAC but not HbAS is associated with an improved birth outcome in pregnant women with documented PAM. Higher-birthweight newborns from HbAC mothers may have a survival advantage that contributes to the natural selection of HbC in malaria-endemic areas.

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Oxidative insult can induce malaria-protective trait of sickle and fetal erythrocytes

Cited by 50 publications

References 74 publications

Resistance to Plasmodium falciparum in sickle cell trait erythrocytes is driven by oxygen-dependent growth inhibition

Resistance to Plasmodium falciparum in sickle cell trait erythrocytes is driven by oxygen-dependent growth inhibition

Hemoglobin variants shape the distribution of malaria parasites in human populations and their transmission potential

Heterozygous HbAC but not HbAS is associated with higher newborn birthweight among women with pregnancy-associated malaria

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