Abstract
ObjectivesThe sickle‐cell trait phenotype is associated with protection from malaria. Multiple molecular mechanisms have been proposed to explain this protection, but the role of the host immune system has been poorly investigated. We hypothesised that cellular immunity to malaria may develop differently in sickle‐cell trait children (HbAS) and children with normal haemoglobin (HbAA) repeatedly exposed to Plasmodium falciparum (Pf).MethodsPaired samples collected prior to the Pf transmission season and during the first malaria episode of the ensuing transmission season from HbAS and HbAA children were analysed by multiplex bead‐based assay and comprehensive multi‐dimensional flow cytometry profiling.ResultsCellular immune profiles were enriched in HbAS relative to HbAA children before the start of the Pf transmission season, with a distinct NK subset. These cells were identified as a novel subset of memory‐activated NK cells characterised by reduced expression of the ecto‐enzyme CD38 as well as co‐expression of high levels of HLA‐DR and CD45RO. The frequency of this NK subset before the transmission season was negatively correlated with parasite density quantified during the first malaria episode of the ensuing transmission season. Functional assessment revealed that these CD38dim CD45RO+ HLA‐DR+ NK cells represent a important source of IFN‐γ.ConclusionOur data suggest that this novel memory‐activated NK cell subset may contribute to an accelerated and enhanced IFN‐γ‐mediated immune response and to control of parasite density in individuals with the sickle‐cell trait. This distinct cellular immune profile may contribute to predispose HbAS children to a relative protection from malaria.
Highlights
The sickle-cell trait phenotype results from the heterodimerisation of normal haemoglobin (Hb) A with Hb presenting the b6 Glu ? Val single amino acid substitution known as HbS
To investigate potential immune mechanisms involved in the relative protection from malaria associated with the sickle-cell trait phenotype, we first compared the capacity of peripheral blood mononuclear cells (PBMCs) isolated from HbAS and HbAA children repeatedly exposed to Plasmodium falciparum (Pf) to respond to stimulation
Our study suggests that memoryactivated natural killer (NK) cells present before the start of the Pf transmission season may contribute to control parasites and delay the onset of the malaria episode in HbAS children by producing an accelerated and enhanced IFN-c response
Summary
The sickle-cell trait phenotype results from the heterodimerisation of normal haemoglobin (Hb) A with Hb presenting the b6 Glu ? Val single amino acid substitution known as HbS. Whereas the homodimerisation of mutated HbS is responsible for the sickle-cell disease, which is characterised by a chronic haemolytic anaemia, no severe conditions are associated with the sicklecell trait phenotype (HbAS). A number of molecular mechanisms have been proposed to explain the relative protection from malaria displayed by HbAS individuals, including parasite growth inhibition in hypoxic condition,[11,12,13,14] enhanced splenic clearance,[13,15,16] altered cytoadherence,[17,18,19] translocation of HbS-specific parasite growth-inhibiting microRNAs,[20] induction of haem oxygenase-121 and HbS polymerisationdependent parasite growth inhibition.[18] A role for the host immune system in the sickle-cell trait phenotype-associated protection has been tentatively proposed, but this has been poorly explored.[22,23,24,25] Few studies have considered the importance of humoral immunity,[26,27,28,29,30] but to the best of our knowledge, there has been no investigation of the role of host cellular immunity in the relative protection of HbAS individuals from malaria
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