NK cells inhibit Plasmodium falciparum growth in red blood cells via antibody-dependent cellular cytotoxicity

Abstract

Antibodies acquired naturally through repeated exposure to Plasmodium falciparum are essential in the control of blood-stage malaria. Antibody-dependent functions may include neutralization of parasite–host interactions, complement activation, and activation of Fc receptor functions. A role of antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells in protection from malaria has not been established. Here we show that IgG isolated from adults living in a malaria-endemic region activated ADCC by primary human NK cells, which lysed infected red blood cells (RBCs) and inhibited parasite growth in an in vitro assay for ADCC-dependent growth inhibition. RBC lysis by NK cells was highly selective for infected RBCs in a mixed culture with uninfected RBCs. Human antibodies to P. falciparum antigens PfEMP1 and RIFIN were sufficient to promote NK-dependent growth inhibition. As these results implicate acquired immunity through NK-mediated ADCC, antibody-based vaccines that target bloodstream parasites should consider this new mechanism of action.

From the “missing self” hypothesis to adaptive NK cells: Insights of NK cell-mediated effector functions in immune surveillance

“…NK cell‐mediated ADCC has been well recognized through its implication in the killing of tumor cells and virus‐infected cells. A recent study has provided evidence that NK cells can inhibit Plasmodium falciparum by lysing infected red blood cells via ADCC . This finding highlights the importance of NK cells in boosting adaptive immunity, not only to control viral infections but also parasites.…”

Longitudinal analysis of naturally acquired antibodies to PfEMP1 CIDR domain variants and their association with malaria protection

“…PfEMP1 variants containing domains of the CIDRα1 class generally bind to EPCR on endothelial cells and are associated with severe malaria (10), whereas variants containing domains of the CIDRα2-6 classes bind to CD36 present on several host cell types, including microvascular endothelial cells, mononuclear phagocytes, and platelets (16, 37). Antibodies targeting these PfEMP1 domains can potentially disrupt adhesion of IEs to host receptors but can also facilitate IE clearance via opsonization and phagocytosis or antibody-mediated cytotoxicity (10, 38, 39). Consistent with a prior study conducted in a Tanzanian cohort (28), we observed early acquisition of IgG antibodies against EPCR-binding PfEMP1 variants of the CIDRα1 domain class relative to CD36-binding variants in both age-stratified cross-sectional and longitudinal analyses.…”

Antibody effector functions in malaria and other parasitic diseases: a few needles and many haystacks

“…There is little evidence that antibodies to infected erythrocytes stimulate monocytes or neutrophils to produce antibody‐dependent respiratory burst, in contrast to antibody‐dependent respiratory burst following ingestion of opsonized merozoites (discussed earlier). Antibodies toward infected erythrocytes can also activate natural killer cells, resulting in degranulation and cytokine production, leading to parasite lysis and growth inhibition . Antibody‐dependent interactions with natural killer cells by infected erythrocytes are dominated by a subset of cells called adaptive natural killer cells .…”