Cytoadhesion of Plasmodium falciparum infected erythrocytes to gC1qR has been associated with severe malaria, but the parasite ligand involved is currently unknown. To assess if binding to gC1qR is mediated through the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, we analyzed by static binding assays and qPCR the cytoadhesion and var gene transcriptional profile of 86 P. falciparum isolates from Mozambican children with severe and uncomplicated malaria, as well as of a P. falciparum 3D7 line selected for binding to gC1qR (Pf3D7gC1qR). Transcript levels of DC8 correlated positively with cytoadhesion to gC1qR (rho = 0.287, P = 0.007), were higher in isolates from children with severe anemia than with uncomplicated malaria, as well as in isolates from Europeans presenting a first episode of malaria (n = 21) than Mozambican adults (n = 25), and were associated with an increased IgG recognition of infected erythrocytes by flow cytometry. Pf3D7gC1qR overexpressed the DC8 type PFD0020c (5.3-fold transcript levels relative to Seryl-tRNA-synthetase gene) compared to the unselected line (0.001-fold). DBLβ12 from PFD0020c bound to gC1qR in ELISA-based binding assays and polyclonal antibodies against this domain were able to inhibit binding to gC1qR of Pf3D7gC1qR and four Mozambican P. falciparum isolates by 50%. Our results show that DC8-type PfEMP1s mediate binding to gC1qR through conserved surface epitopes in DBLβ12 domain which can be inhibited by strain-transcending functional antibodies. This study supports a key role for gC1qR in malaria-associated endovascular pathogenesis and suggests the feasibility of designing interventions against severe malaria targeting this specific interaction.
Author Summary Plasmodium falciparum sequesters in vital organs. This phenomenon mediated by cytoadhesion of infected-erythrocytes to host receptors in the microvasculature, contributes to the development of severe malaria. Although cytoadhesion to Endothelial Protein-C Receptor has a central role in severe malaria, other host receptors are also likely to be involved. Our results generated by the analysis of P. falciparum isolates from Mozambican patients and laboratory parasite lines indicate that a specific domain (DBLβ12) from DC8-type PfEMP1s can bind to the human receptor gC1qR, previously associated with severe malaria. Our findings revealed that antibodies against PfEMP1 could provide strain-transcending inhibition of gC1qR-binding. Overall, these results support a key role for the adhesion to gC1qR in malaria-associated endovascular pathogenesis and the feasibility of new interventions targeting this specific interaction.