Antibodies targeting merozoites induce natural killer cell degranulation and interferon gamma secretion and are associated with immunity against malaria

Abstract

Natural killer cells are potent immune effectors that can be activated via antibody mediated Fc receptor engagement. Using multiparameter flow cytometry, we found that natural killer (NK) cells degranulate and release IFNγ upon stimulation with antibody-opsonized Plasmodium falciparum merozoites. Antibody-dependent NK activity (Ab-NK) was largely strain-transcending and enhanced the inhibition of invasion into erythrocytes. Ab-NK was associated with the successful control of parasitemia following experimental malaria challenge in African adults. In an independent cohort study in children, Ab-NK increased with age, was boosted by concurrent falciparum infections and associated with a lower risk of clinical episodes of malaria. Nine of 14 vaccine candidates tested induced Ab-NK including some less well-studied antigens - P41, P113, MSP11, RHOPH3, and Pf_11363200. These data highlight an important role for ab-NK in immunity against malaria and provide a new mechanism for the evaluation of vaccine candidatesOne Sentence SummaryAntibody-dependent natural killer activation is induced by merozoites and associated with immunity against malaria

Full-length merozoite surface protein 1 ofPlasmodium falciparumis a major target of protective immunity following controlled human malaria infections

“…The finding that the entire MSP1 molecule was the target of functional antibodies was not surprising and is supported by early and more recent studies (Jäschke et al, 2017;Woehlbier et al, 2006). The most striking results were that anti-MSP1FL antibodies almost completely recapitulated our recent data identifying Fc-mediated mechanisms targeting merozoites as strong correlates of protective immunity (Nkumama et al, 2022;Odera et al, 2021). These data are consistent with the fact that MSP1 is the most abundant protein on the surface of merozoites (Gilson et al, 2006).…”

Breadth of Fc-mediated effector function delineates grades of clinical immunity following human malaria challenge

“…We and others have shown that invasion inhibition by anti-merozoite antibodies was significantly increased in the presence of NK cells (Odera et al ., 2021) and complement (Boyle et al ., 2015) suggesting that Fc-mediated effector mechanisms are induced rapidly and can target merozoites before invasion. Additionally, Boyle et al, 2015 showed that GIA activity was not associated with protection but growth inhibition in the presence of complement proteins was associated with protection.…”

“…For Fc-effector function, we measured ADRB, AbC’, Ab-NK, and opsonic phagocytosis of merozoites and rings stage parasites. The Ab-NK assay had two readouts: degranulation (the proportion of NK cells that were CD107a + ) and IFNγ production (the proportion of NK cells that were IFNγ + , Odera et al ., 2021).…”

“…Antibodies inducing Fc-effector function against merozoite stage parasites are acquired with age and correlated with protection in independent cohort studies (Joos et al ., 2010; Hill et al .,2013; Osier et al ., 2014a; Boyle et al ., 2015; Tiendrebeogo et al ., 2015). However, each study examined a single cellular or soluble effector such as neutrophils (Joos et al ., 2010; Feng et al ., 2021), monocytes (Hill et al ., 2013; Osier et al ., 2014a), natural killer cells (Odera et al .,2021) or complement (Boyle et al ., 2015; Reiling et al ., 2019) in a distinct study population. Neither the breadth, nor the relative importance of individual Fc-effector functions have been analyzed concurrently in a well-characterized experimental malaria study in humans.…”

“…We used this framework to test the largest panel of Fc-mediated functional assays targeting P. falciparum merozoites in a single study; antibody-dependent respiratory burst from neutrophils (Joos et al ., 2010;), antibody-dependent complement fixation (AbC’, Boyle et al .,2015), antibody-mediated natural killer cells activation (Ab-NK, Odera et al ., 2021), and opsonic phagocytosis of both merozoites (Osier et al ., 2014a) and ring stage parasites (Musasia et al ., 2022). We also measured the gold-standard growth inhibitory activity (Persson et al, 2006) and asked which of these seven assays best predicted the primary clinical outcome, defined as the need for anti-malarial treatment post challenge (Kapulu et al ., 2021).…”