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Updated: Aug 29, 2026
Measuring Naturally Acquired Phagocytosis-Inducing Antibodies to Plasmodium falciparum Parasites by a Flow Cytometry-Based Assay
Published on: August 6, 2020
Gravidity-dependent protection against placental malaria is associated with enhanced natural killer cell-mediated
Savannah N Lewis1, Alea Delmastro2, Mary Lopez-Perez3
1Department of Medicine, Stanford University, Stanford, CA, USA; Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.
Background:
Placental malaria disproportionately affects primigravid women and is a leading cause of morbidity in endemic settings. IgG specific to VAR2CSA, a placenta-binding Plasmodium falciparum protein, accumulates with successive pregnancies, but protective mechanisms remain incompletely understood. We investigated whether natural killer antibody-dependent cellular activation (NK-ADCA) was acquired in a gravidity-dependent manner and associated with improved birth outcomes.
Methods:
We characterised second trimester NK-ADCA and VAR2CSA-specific antibody features among pregnant women in Eastern Uganda (NCT04336189). NK-ADCA (n = 53) against VAR2CSA-expressing P. falciparum-infected erythrocytes was assessed using primary NK cells with autologous or pooled donor plasma with characterised IgG Fc-fucosylation profiles. VAR2CSA-specific IgG abundance and Fc-fucosylation (n = 71) were quantified by ELISA and mass spectrometry. Responses were compared across gravidity and associations with placental malaria and birth weight determined.
Findings:
NK-ADCA increased significantly with gravidity (median 31.0% in multigravida [n = 20] vs. 11.7 in primigravid [n = 18], p = 0.0014) and correlated with reduced placental malaria severity (rs = -0.28, p = 0.043) and higher birth weight (rs = 0.52, p = 1 × 10-4). NK cell phenotypes did not differ across gravidities; instead, gravidity-dependent NK-ADCA was associated with VAR2CSA-specific IgG abundance (rs = 0.50, p = 0.00014) and reduced Fc-fucosylation (rs = -0.69, p = 1.2 × 10-8). Depletion of VAR2CSA-specific antibodies reduced NK-ADCA in multigravid but not primigravid plasma. A CD56neg adaptive-like NK subset (CD85j+FcεRIγ-NKG2C-) mediated most NK-ADCA and was preferentially activated by Fc-afucosylated antibodies.
Interpretation:
Gravidity-dependent protection against placental malaria was associated with enhanced NK-ADCA driven by accumulation of Fc-afucosylated VAR2CSA-specific antibodies, identifying NK-ADCA as a potentially important component of protective immunity to placental malaria.
Funding:
This work was supported by the National Institutes of Health, the Blavatnik Family Foundation, the Stanford University Office of the Vice Provost for Graduate Education, the Stanford Maternal and Child Health Research Institute, and the Danish Research Council for Development Research.
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