Impact of sickle cell trait hemoglobin in Plasmodium falciparum-infected erythrocytes
Sickle cell trait (HbAS) confers protection against severe Plasmodium falciparum malaria but has little effect on infection rates per se. The reason for this is not fully understood. However, it appears to involve impaired parasite survival at the low oxygen tensions prevailing in the postcapillary venules where P. falciparum-infected erythrocytes (IEs) often accumulate. This IE sequestration is mediated by parasite-encoded IE surface ligands, primarily PfEMP1. Different variants of this family of proteins bind to host receptors with different tissue distributions. We hypothesized that P. falciparum parasites modulate PfEMP1 expression to enhance their survival by altering IE tissue distribution in HbAS hosts. To test this, we studied PfEMP1 expression in parasites maintained in vitro in HbAS and HbAA erythrocytes. We found that parasite survival and PfEMP1 expression were reduced in HbAS IEs, particularly at low oxygen tensions, without obvious qualitative differences in PfEMP1 expression between HbAA and HbAS IEs. In contrast, parasites growing in HbAS erythrocytes increased their transcription of pfsa2, a parasite gene hypothesized to be under HbS-dependent selection. Taken together, our findings support the hypothesis of quantitative but not qualitative modulation of PfEMP1 expression as a parasite strategy for coping with HbAS-related host resistance. Moreover, it provides a hint at the role of Pfsa2 in parasite adaptation to HbAS and highlights the importance of further research.