Antibody-dependent NK cell control of Plasmodium falciparum infection

Plasmodium falciparum (P.f) infection is a major cause of morbidity and mortality world-wide where symptoms and death occur as a result of the blood stage of the P.f. life cycle. To date, there is no effective blood stage malarial vaccine. Natural Killer (NK) cells are key players in the control of hematopoietic cancers and viral infections, however their role in blood stage malaria is unknown. We undertook a comprehensive analysis of NK cell phenotype and function in a cohort of subjects from a malaria clinical study in Mali, Africa. Using an unbiased analysis of different NK cell subsets, we found that ‘adaptive’ NK cells (lacking FcR gamma chain) increased with age and correlated with reduced malaria risk. Adaptive NK cells had enhanced antibody dependent cellular cytotoxicity (ADCC) function relative to other NK cell subsets. Antibodies are known to be protective in malaria, however the mechanism of this protection is still being elucidated. We hypothesized the protective mechanism of adaptive NK cells may be adaptive NK cells pairing with malaria antibodies to clear infected RBCs via ADCC. In a parallel study, we have shown that NK cells from healthy US donors can inhibit the growth of Plasmodium falciparum 3D7 strain in vitro in the presence of IgG from malaria-exposed adults. Adaptive NK cells from Mali also have enhanced ADCC to infected RBCs. This work indicates that protective antibodies may pair with the strong ADCC activity of adaptive NK cells to protect human subjects from malaria symptoms. These findings thus open a new avenue for vaccine development exploring antibody-dependent cell mediated killing of malaria parasites.