RESUMEN
BACKGROUND: The Dantu blood group variant protects against P. falciparum infections but its wider consequences have not been previously explored. Here, we investigate the impact of Dantu on susceptibility to bacteraemia. METHODS: We conducted a case-control study in children presenting with community-acquired bacteraemia to Kilifi County Hospital in Kenya between 1998 and 2010. We used logistic regression to test for associations between the Dantu marker SNP rs186873296 A>G and both all-cause and pathogen-specific bacteraemia under an additive model. We used date of admission as a proxy measure of malaria transmission intensity, given known differences in malaria prevalence over the course of the study. RESULTS: Dantu was associated with protection from all-cause bacteraemia (OR=0.81, p=0.014), the association being greatest in homozygotes (OR=0.30, p=0.013). This protection was shared across the major bacterial pathogens but, notably, was only significant during the era of high malaria-transmission pre-2003 (OR=0.79, p=0.023). CONCLUSIONS: Consistent with previous studies showing the indirect impact on bacteraemia risk of other malaria-associated red cell variants, our study also shows that Dantu is protective against bacteraemia via its effect on malaria risk. Dantu does not appear to be under balancing selection through an increased risk of bacterial infections.
RESUMEN
Dantu erythrocytes, which express a hybrid glycophorin B/A protein, are protective against severe malaria. Recent studies have shown that Dantu impairs Plasmodium falciparum invasion by increasing erythrocyte membrane tension, but its effects on pathological host-parasite adhesion interactions such as rosetting, the binding of uninfected erythrocytes to P. falciparum-infected erythrocytes, have not been investigated previously. The expression of several putative host rosetting receptors-including glycophorin A (GYPA), glycophorin C (GYPC), complement receptor 1 (CR1), and band 3, which complexes with GYPA to form the Wrightb blood group antigen-are altered on Dantu erythrocytes. Here, we compare receptor expression, and rosetting at both 1 hour and 48 hours after mixing with mature trophozoite-stage Kenyan laboratory-adapted P. falciparum strain 11019 parasites in Dantu and non-Dantu erythrocytes. Dantu erythrocytes showed lower staining for GYPA and CR1, and greater staining for band 3, as observed previously, whereas Wrightb and GYPC staining did not vary significantly. No significant between-genotype differences in rosetting were seen after 1 hour, but the percentage of large rosettes was significantly less in both Dantu heterozygous (mean, 16.4%; standard error of the mean [SEM], 3.2) and homozygous donors (mean, 15.4%; SEM, 1.4) compared with non-Dantu erythrocytes (mean, 32.9%; SEM, 7.1; one-way analysis of variance, P = 0.025) after 48 hours. We also found positive correlations between erythrocyte mean corpuscular volume (MCV), the percentage of large rosettes (Spearman's rs = 0.5970, P = 0.0043), and mean rosette size (rs = 0.5206, P = 0.0155). Impaired rosetting resulting from altered erythrocyte membrane receptor expression and reduced MCV might add to the protective effect of Dantu against severe malaria.