The Dantu blood group prevents parasite growth in vivo: Evidence from a controlled human malaria infection study

Abstract

Background:The long co-evolution of Homo sapiens and Plasmodium falciparum has resulted in the selection of numerous human genetic variants that confer an advantage against severe malaria and death. One such variant is the Dantu blood group antigen, which is associated with 74% protection against severe and complicated P. falciparum malaria infections in homozygous individuals, similar to that provided by the sickle haemoglobin allele (HbS). Recent in vitro studies suggest that Dantu exerts this protection by increasing the surface tension of red blood cells, thereby impeding the ability of P. falciparum merozoites to invade them and reducing parasite multiplication. However, no studies have yet explored this hypothesis in vivo.Methods:We investigated the effect of Dantu on early phase P. falciparum (Pf) infections in a controlled human malaria infection (CHMI) study. 141 sickle-negative Kenyan adults were inoculated with 3.2 × 103 aseptic, purified, cryopreserved Pf sporozoites (PfSPZ Challenge) then monitored for blood-stage parasitaemia for 21 days by quantitative polymerase chain reaction (qPCR)analysis of the 18S ribosomal RNA P. falciparum gene. The primary endpoint was blood-stage P. falciparum parasitaemia of ≥500/μl while the secondary endpoint was the receipt of antimalarial treatment in the presence of parasitaemia of any density. On study completion, all participants were genotyped both for Dantu and for four other polymorphisms that are associated with protection against severe falciparum malaria: α+-thalassaemia, blood group O, G6PD deficiency, and the rs4951074 allele in the red cell calcium transporter ATP2B4.Results:The primary endpoint was reached in 25/111 (22.5%) non-Dantu subjects in comparison to 0/27 (0%) Dantu heterozygotes and 0/3 (0.0%) Dantu homozygotes (p=0.01). Similarly, 49/111 (44.1%) non-Dantu subjects reached the secondary endpoint in comparison to only 7/27 (25.9%) and 0/3 (0.0%) Dantu heterozygotes and homozygotes, respectively (p=0.021). No significant impacts on either outcome were seen for any of the other genetic variants under study.Conclusions:This study reveals, for the first time, that the Dantu blood group is associated with high-level protection against early, non-clinical, P. falciparum malaria infections in vivo. Learning more about the mechanisms involved could potentially lead to new approaches to the prevention or treatment of the disease. Our study illustrates the power of CHMI with PfSPZ Challenge for directly testing the protective impact of genotypes previously identified using other methods.Funding:The Kenya CHMI study was supported by an award from Wellcome (grant number 107499). SK was supported by a Training Fellowship (216444/Z/19/Z), TNW by a Senior Research Fellowship (202800/Z/16/Z), JCR by an Investigator Award (220266/Z/20/Z), and core support to the KEMRI-Wellcome Trust Research Programme in Kilifi, Kenya (203077), all from Wellcome. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.Clinical trial number:NCT02739763

Adaptive admixture atACKR1(the Duffy locus) may have shapedPlasmodium vivaxprevalence in Oman

“…Lastly, we investigated copy number variation at the cluster of glycophorin genes that determine the MNS blood group. A complex structural rearrangement affecting both GYPA and GYPB and encoding the Dantu antigen has been associated with protection from severe P. falciparum malaria but is common only in coastal east African populations 47,79,80 . Applying a Hidden Markov Model to infer copy number from coverage data across this locus (including a mappability filter as in Leffler et al 2017 47 ) and looking at tag SNPs, we identified one Omani and one Qatari individual carrying the Dantu structural variant (Supplementary Figure 5; Supplementary Table 5), suggesting it has likely spread to the southern Arabian Peninsula through east African admixture.…”

“…There are numerous different SNVs that cause G6PD deficiency found in populations throughout the world 72 as well as beta-thalassemias, which are also at relatively low frequency potentially due to balancing selection. We identify the P. falciparum -associated Dantu structural variant (SV), which has only been reported at appreciable frequency in coastal East Africa 47,79,80 . However, it was carried by a single Omani individual who had a high proportion of African ancestry genome-wide, suggesting it may result from more recent admixture.…”

“…47,79,80 . However, it was carried by a single Omani individual who had a high proportion of African ancestry genome-wide, suggesting it may result from more recent admixture.Our findings support the repeated convergent selection of Fy ES in diverse African admixed populations with remarkably similar strength and pattern of selection, despite different timing and geographical and ecological milieus.…”

Higher multiplication rates ofPlasmodium falciparumin isolates from hospital cases compared with community infections

“…Even if there were strong causality, this correlation is not expected to be absolute, as there are many other determinants of parasitaemia in the peripheral blood at a given time, and some community infections at low parasitaemia could potentially go on to become high parasitaemia infection leading to hospitalisation. The direction of causality also remains to be established, as variation in the in vivo blood-stage environment during infection, including differences in host erythrocytes, iron availability and inflammatory immune responses [20-22], may stimulate parasites to adjust their intrinsic growth rate phenotypes which then persist in culture.…”