Maternal Fc-mediated non-neutralizing antibody responses correlate with protection against congenital human cytomegalovirus infection
Eleanor C. Semmes, … , Kyle M. Walsh, Sallie R. Permar
Eleanor C. Semmes, … , Kyle M. Walsh, Sallie R. Permar
Published June 28, 2022
Citation Information: J Clin Invest. 2022;132(16):e156827. https://doi.org/10.1172/JCI156827.
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Maternal Fc-mediated non-neutralizing antibody responses correlate with protection against congenital human cytomegalovirus infection

Abstract

Human cytomegalovirus (HCMV) is the most common congenital infection and a leading cause of stillbirth, neurodevelopmental impairment, and pediatric hearing loss worldwide. Development of a maternal vaccine or therapeutic to prevent congenital HCMV has been hindered by limited knowledge of the immune responses that protect against HCMV transmission in utero. To identify protective antibody responses, we measured HCMV-specific IgG binding and antiviral functions in paired maternal and cord blood sera from HCMV-seropositive transmitting (n = 41) and non-transmitting (n = 40) mother-infant dyads identified via a large, US-based, public cord blood bank. We found that high-avidity IgG binding to HCMV and antibody-dependent cellular phagocytosis (ADCP) were associated with reduced risk of congenital HCMV infection. We also determined that HCMV-specific IgG activation of FcγRI and FcγRII was enhanced in non-transmitting dyads and that increased ADCP responses were mediated through both FcγRI and FcγRIIA expressed on human monocytes. These findings suggest that engagement of FcγRI/FcγRIIA and Fc effector functions including ADCP may protect against congenital HCMV infection. Taken together, these data can guide future prospective studies on immune correlates against congenital HCMV transmission and inform HCMV vaccine and immunotherapeutic development.

Authors

Eleanor C. Semmes, Itzayana G. Miller, Courtney E. Wimberly, Caroline T. Phan, Jennifer A. Jenks, Melissa J. Harnois, Stella J. Berendam, Helen Webster, Jillian H. Hurst, Joanne Kurtzberg, Genevieve G. Fouda, Kyle M. Walsh, Sallie R. Permar

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Figure 6

HCMV-specific IgG activation of FcγRI, FcγRIIA ,and FcγRIIB is increased in non-transmitting compared with transmitting mother-infant dyads.

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HCMV-specific IgG activation of FcγRI, FcγRIIA ,and FcγRIIB is increased...
HCMV-specific IgG activation of FcγRs was measured using maternal and cord blood sera from HCMV transmitting (red circles, n = 41) and non-transmitting (blue diamonds, n = 40) mother-infant dyads. For quantification of HCMV-specific IgG activation of FcγRs, mouse BW cell lines stably expressing chimeric human FcγRs fused to a mouse CD3ζ signaling domain were co-cultivated with virus:serum immune complexes for 20 hours. Activation of FcγRs by immune complexes triggered CD3ζ signaling and mouse IL-2 secretion, which was measured by ELISA as a quantitative readout of HCMV-specific IgG signaling through host FcγRs. (A–C) Flow cytometry of BW cell lines including unstained cells, isotype control, anti-FcγRI/CD64, anti-FcγRII/CD32, and anti-FcγRIII/CD16 PE-conjugated antibodies. (D–F) HCMV-specific IgG activation of (D) FcγRIA, (E) FcγRIIA, (F) FcγRIIB in transmitting versus non-transmitting dyads and within paired maternal and cord blood sera. (G–I) Spearman’s correlations between HCMV-specific IgG FcγR activation and ADCP. Horizontal black bars denote median. P values for Mann-Whitney U test (D–F between groups) and Wilcoxon’s signed-rank test (D–F within dyads). *P < 0.05, **P < 0.01, ***P < 0.001.