Sickle cell status skews malaria parasite genotype at infection

Sickle cell hemoglobin (HbS) confers protection against symptomatic malaria caused by Plasmodium falciparum . HbS carriers with symptomatic malaria harbour parasites enriched for 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 school children in a region of high malaria transmission region in Cameroon. Analysing parasite Pfsa and 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 Pfsa + alleles at 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, where HbS has a protective effect prior to symptoms against Pfsa- parasites and Pfsa+ alleles may contribute to lower rates of symptomatic disease in HbS carriers. HbS protection against malarial disease should consider both resistance and tolerance and ongoing co-evolution with parasites.