Sickle cell haemoglobin status shapes malaria parasite genotype in asymptomatic infections.

Sickle cell haemoglobin (HbS) confers protection against symptomatic malaria caused by Plasmodium falciparum. HbS carriers with symptomatic malaria harbour parasites enriched for P. falciparum sickle-associated alleles (Pfsa+), which appear to partially overcome HbS-mediated protection, but their role in asymptomatic infections is unclear. Here we conducted a cross-sectional survey of 2,246 healthy schoolchildren in a region of high malaria transmission in Cameroon. Analysing the parasite Pfsa and the human HbS genotypes for 1,701 asymptomatic P. falciparum infections confirmed that heterozygous HbS (HbAS) and homozygous non-HbS (HbAA) genotypes have similar rates of asymptomatic infection. However, the HbS genotype is strongly associated with parasites carrying the Pfsa+ alleles at the Pfsa1 and Pfsa3 loci, indicating a selective advantage for these alleles in HbS carriers. Our findings reveal that the protective effect of HbS is complex: HbS has a protective effect before symptoms appear against Pfsa- parasites and Pfsa+ alleles may contribute to the lower rates of symptomatic disease observed in HbS carriers. In HbS-mediated protection against malaria, both resistance and tolerance and ongoing co-evolution with parasites should be considered.