Ficolin-1 in pediatric Plasmodium falciparum malaria and its possible role in parasite clearance and anemia

Abstract

Plasmodium falciparum malaria causes significant disease, especially in young children. A successful immune response to P. falciparum is a major determinant of clinical outcome. The ficolins are a family of lectins that act as pattern recognition molecules and can activate the lectin complement pathway and may promote inflammation and facilitate opsonization and lysis of pathogens. Here, we have investigated the potential roles of ficolin-1 and ficolin-2 in the context of P. falciparum infection. We measured ficolin-1 and ficolin-2 concentrations in plasma from Malawian children presenting with uncomplicated or severe malaria or healthy controls (HCs) by ELISA. Using flow cytometry, we assessed whether ficolin-1 could bind to infected red blood cells (iRBCs) and whether it binds sialic acid on the iRBCs. Ficolin-1 and ficolin-2 plasma levels were measured in children from all clinical groups. Compared to HCs (reference), Ficolin-1 concentrations in plasma were higher in children with uncomplicated (geometric mean ratio: 1.88; 95% confidence interval [CI]: 1.25-2.82) and severe malaria (1.65; 95% CI: 1.10-2.46). Ficolin-1 levels were positively associated with peripheral blood monocyte (1.30; 1.02-1.67) and neutrophil counts (1.06; 1.00-1.13). Ficolin-2 was not associated with malaria. Hemoglobin levels were negatively associated with ficolin-1 (-0.38; -0.68 to -0.09) and ficolin-2 (-0.36; -0.68 to -0.04). Ficolin-1 bound more to iRBCs compared to uninfected RBCs, and binding was reduced in a ficolin-1 mutant that did not bind to sialic acid. These results highlight a largely overlooked role for ficolin-1 in the immune response to P. falciparum infection and point to a potential role for lectins contributing to parasite clearance and anaemia.

Keywords: Malawi; Plasmodium falciparum; ficolin; severe malaria.

Fig 1

Ficolin-1 binding to Plasmodium falciparum infected red blood cells (iRBCs). (A) More ficolin-1 binds iRBC compared to uninfected RBCs. This was consistently seen for parasite isolates expressing different PfEMP1s (CS2 and E8B) and a mutant (CS2SBP1KO) which does not export PfEMP1 to the surface of the iRBCs. (B) The % of iRBCs (E8B strain) and RBCs which bound ficolin-1 was reduced when a mutant Y271F (which does not bind sialic acid-containing glycans) was used. Each data point is a mean of an individual experiment done in triplicate. Each experiment was repeated three to six times with different RBC donors. Bars are mean (SEM), means were compared using paired t-tests.