Acquisition of Fc-afucosylation of PfEMP1-specific IgG is age-dependent and associated with clinical protection against malaria

Abstract

Abstract Protective immunity to malaria depends on acquisition of parasite-specific antibodies, with Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) being one of the most important target antigens. The effector functions of PfEMP1-specific IgG include inhibition of infected erythrocyte (IE) sequestration and opsonization of IEs for cell-mediated destruction. IgG glycosylation modulates antibody functionality, with increased affinity to FcγRIIIa for IgG lacking fucose in the Fc region (Fc-afucosylation). We report here that selective Fc‑afucosylation of PfEMP1-specific IgG1 increases with age in P. falciparum-exposed children and is associated with reduced risk of anemia and parasitemia, independent of the IgG levels. A similar association was found for children having PfEMP1-specific IgG1 inducing multiple effector functions against IEs. Our findings provide new mechanistic insights regarding protective immunity to malaria and highlight the importance of cell-mediated destruction of IgG-opsonized IEs.