Anti-merozoite antibodies induce natural killer cell effector function and are associated with immunity against malaria

Odera, Dennis; Tuju, James; Mwai, Kennedy; Nkumama, Irene; Fürle, Kristin; Chege, Timothy; Kimathi, Rinter; Diehl, Stefan; Musasia, Fauzia; M, Rosenkranz; Njuguna, Patricia; Hamaluba, Mainga; Kapulu, Melissa; Frank, Roland; Osier, Faith; Abdi, Abdirahman; Che, Primus; Laurent, Zaydah R. de; Jao, Irene; Kamuya, Dorcas; Kamuyu, Gathoni; Makale, Johnstone; Murungi, Linda M.; Musyoki, Jennifer; Muthui, Michelle; Mwacharo, Jedidah; Kariuki, Silvia N.; Mwanga, Daniel; Mwongeli, Joyce; Ndungu, Francis M.; Njue, Maureen; Nyangweso, George; Kimani, Domitila; Ngoi, Joyce M.; Musembi, Janet; Ngoto, Omar; Otieno, Edward; Ooko, Michael; Shangala, Jimmy; Wambua, Juliana; Mohammed, Khadija Said; Omuoyo, Donwilliams O.; Mosobo, Moses; Kibinge, Nelson; Kinyanjui, Sam; Bejon, Philip; Lowe, Brett; Marsh, Kevin; Marsh, Vicki; Abebe, Yonas; Billingsley, Peter F.; Sim, B. Kim Lee; Hoffman, Stephen L.; James, Eric R.; Richie, Thomas L.; Audi, Agnes; Olewe, Fredrick; Oloo, James Alan; Ong’echa, John Michael; Ongas, Martin O.; Koskei, Nelly; Bull, Peter C.; Hodgson, Susanne H.; Kivisi, Cheryl Andisi; Imwong, Mallika; Murphy, Sean C.; Ogutu, Bernhards; Tärning, Joel; Winterberg, Markus; Williams, Thomas N.

doi:10.1126/scitranslmed.abn5993

Cited by 17 publications

(21 citation statements)

References 64 publications

(138 reference statements)

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“…The level of NK cell degranulation in variant V1 was comparable to that of MSP1. This activity has been recently demonstrated to be an important mechanism of action of antibodies in malaria in the context of both naturally acquired immunity and vaccine studies (35,60,61) We detected extensive variation in the serological responses to the 27 common variants of ARMA identified in African isolates. This level of diversity was remarkable given that there were only 1 -4 amino acid differences between variants.…”

Section: Discussionmentioning

confidence: 76%

“…This experiment was performed using a protocol that was recently developed in our laboratory (35). Briefly, following coating 30 ng/ml recombinant proteins; V1, V2 and MSP1 (control), in 96-well culture plate at 4°C overnight, the wells were washed with PBS and blocked for 2 hours at 37°C with 1% casein in PBS.…”

Section: Functional Antibody Assays Nk Cell Degranulation Assaymentioning

confidence: 99%

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Characterization of a novel Plasmodium falciparum merozoite surface antigen and potential vaccine target

Niaré

Chege

et al. 2023

Front. Immunol.

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IntroductionDetailed analyses of genetic diversity, antigenic variability, protein localization and immunological responses are vital for the prioritization of novel malaria vaccine candidates. Comprehensive approaches to determine the most appropriate antigen variants needed to provide broad protection are challenging and consequently rarely undertaken.MethodsHere, we characterized PF3D7_1136200, which we named Asparagine-Rich Merozoite Antigen (ARMA) based on the analysis of its sequence, localization and immunogenicity. We analyzed IgG and IgM responses against the common variants of ARMA in independent prospective cohort studies in Burkina Faso (N = 228), Kenya (N = 252) and Mali (N = 195) using a custom microarray, Div-KILCHIP.ResultsWe found a marked population structure between parasites from Africa and Asia. African isolates shared 34 common haplotypes, including a dominant pair although the overall selection pressure was directional (Tajima’s D = -2.57; Fu and Li’s F = -9.69; P < 0.02). ARMA was localized to the merozoite surface, IgG antibodies induced Fc-mediated degranulation of natural killer cells and strongly inhibited parasite growth in vitro. We found profound serological diversity, but IgG and IgM responses were highly correlated and a hierarchical clustering analysis identified only three major serogroups. Protective IgG and IgM antibodies appeared to target both cross-reactive and distinct epitopes across variants. However, combinations of IgG and IgM antibodies against selected variants were associated with complete protection against clinical episodes of malaria.DiscussionOur systematic strategy exploits genomic data to deduce the handful of antigen variants with the strongest potential to induce broad protection and may be broadly applicable to other complex pathogens for which effective vaccines remain elusive.

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Section: Discussionmentioning

confidence: 76%

Section: Functional Antibody Assays Nk Cell Degranulation Assaymentioning

confidence: 99%

Characterization of a novel Plasmodium falciparum merozoite surface antigen and potential vaccine target

Niaré

Chege

et al. 2023

Front. Immunol.

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“…It is widely accepted that antibodies play a key role in antimalarial immunity ( Cohen et al, 1961 ; Sabchareon et al, 1991 ) and emerging data highlight the importance of Fc-mediated effector functions for a protective immune response. This includes the recruitment of complement factors ( Boyle et al, 2015 ; Reiling et al, 2019 ) natural killer (NK) cells ( Odera et al, 2023 ), monocytes ( Hill et al, 2013 ; Osier et al, 2014 ; Musasia et al, 2022 ), and neutrophils ( Joos et al, 2010 ). We recently conducted a controlled human malaria infection study in semi-immune Kenyan adults (CHMI-SIKA) ( Kapulu et al, 2022 ) where we showed that antibody-dependent phagocytosis of ring-stage parasites ( Musasia et al, 2022 ) and activity of NK cells against merozoites ( Odera et al, 2023 ) were important functional correlates of protection.…”

Section: Introductionmentioning

confidence: 99%

“…This includes the recruitment of complement factors ( Boyle et al, 2015 ; Reiling et al, 2019 ) natural killer (NK) cells ( Odera et al, 2023 ), monocytes ( Hill et al, 2013 ; Osier et al, 2014 ; Musasia et al, 2022 ), and neutrophils ( Joos et al, 2010 ). We recently conducted a controlled human malaria infection study in semi-immune Kenyan adults (CHMI-SIKA) ( Kapulu et al, 2022 ) where we showed that antibody-dependent phagocytosis of ring-stage parasites ( Musasia et al, 2022 ) and activity of NK cells against merozoites ( Odera et al, 2023 ) were important functional correlates of protection. Furthermore, additional analyses incorporating the full-panel of Fc-dependent and non-Fc mechanisms revealed that the breadth of effector functions targeting merozoites was most strongly associated with protection.…”

Section: Introductionmentioning

confidence: 99%

Full-length MSP1 is a major target of protective immunity after controlled human malaria infection

Rosenkranz,

Nkumama,

Ogwang

et al. 2024

Life Sci. Alliance

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The merozoite surface protein 1 (MSP1) is the most abundant protein on the surface of the invasive merozoite stages ofPlasmodium falciparumand has long been considered a key target of protective immunity. We used samples from a single controlled human malaria challenge study to test whether the full-length version of MSP1 (MSP1FL) induced antibodies that mediated Fc-IgG functional activity in five independent assays. We found that anti-MSP1FLantibodies induced complement fixation via C1q, monocyte-mediated phagocytosis, neutrophil respiratory burst, and natural killer cell degranulation as well as IFNγ production. Activity in each of these assays was strongly associated with protection. The breadth of MSP1-specific Fc-mediated effector functions was more strongly associated with protection than the individual measures and closely mirrored what we have previously reported using the same assays against merozoites. Our findings suggest that MSP1FLis an important target of functional antibodies that contribute to a protective immune response against malaria.

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“…Accordingly, γδ T-cells producing proin ammatory cytokines in response to PfRBC have been linked to protection from parasitaemia (32). Secondly, these innate immune cells directly mediate cellular cytotoxicity against PfRBC, involving release of granzymes and granulysin by degranulation upon exposure to merozoites and PfRBC (33)(34)(35)(36)(37)(38)(39)(40). γδ T-cells and NK are directly activated by PfRBC components (27,29,33,34,(41)(42)(43)(44): via phosphoantigens recognized by γδ T-cells (42,43), and NK sensing of host Hsp70 expression on PfRBC (33), recognition of PfEMP-1 via the activating receptor NKp30 (45) and sensing of microvesicle-transported parasite RNA via the RIG-I-like receptor MDA5 (46).…”

Section: Introductionmentioning

confidence: 99%

Plasmodium falciparum malaria exposure and carriage associate with reduced γδ T-cells and NK cell responses to infected red blood cells in vitro

Kouriba

Daou

Arama

et al. 2023

Preprint

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Background Innate immune cells including γδ T-cells and NK cells are directly activated by Plasmodium falciparum parasites and contribute to the control of parasitaemia. The aim of this study was to determine whether a history of parasite exposure and/or carriage affect innate immune cell responses in vitro to P. falciparum infected red blood cells (PfRBC). Methods Peripheral blood mononuclear cells were collected from 61 Malian children aged 5 to 15 years at the start of the transmission season, and 10 malaria-naïve Dutch adults. Parasite carriage at the start of the transmission season was assessed by PCR and microscopy for Malian children. Peripheral blood mononuclear cells were stimulated with PfRBC to assess cytokine production and degranulation of innate lymphocytes (γδ T-cells, CD3+CD56+ cells and NK cells) by flow cytometry. Results Granzyme B production in response to PfRBC was observed by all three innate cell subsets in Malian children, as were IFNγ production by γδ T-cells and NK cells and γδ T-cell degranulation. However, both IFNγ production and degranulation by γδ T-cells, CD3+CD56+ cells and NK cells were significantly lower compared to malaria-naïve Dutch adults. Moreover, children with ongoing P. falciparuminfection showed significantly reduced PfRBC-specific IFNγ production and degranulation by γδ T-cells and NK cells as compared with those with undetectable parasitaemia by PCR and microscopy. Reduced degranulation responses by γδ T-cells and NK cells were already observed for children with submicroscopic parasitaemia as compared to those with negative PCR. Conclusions Malian children show reduced P. falciparum-specific innate IFNγ production and cytotoxic degranulation, which were further negatively impacted by ongoing infections of microscopic but also submicroscopic parasitaemia.

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Anti-merozoite antibodies induce natural killer cell effector function and are associated with immunity against malaria

Cited by 17 publications

References 64 publications

Characterization of a novel Plasmodium falciparum merozoite surface antigen and potential vaccine target

Characterization of a novel Plasmodium falciparum merozoite surface antigen and potential vaccine target

Full-length MSP1 is a major target of protective immunity after controlled human malaria infection

Plasmodium falciparum malaria exposure and carriage associate with reduced γδ T-cells and NK cell responses to infected red blood cells in vitro

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