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Pathobiont-driven antibody sialylation through IL-10 undermines vaccination
Chih-Ming Tsai, … , Nathan E. Lewis, George Y. Liu
Chih-Ming Tsai, … , Nathan E. Lewis, George Y. Liu
Published December 16, 2024
Citation Information: J Clin Invest. 2024;134(24):e179563. https://doi.org/10.1172/JCI179563.
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Research Article Immunology Infectious disease Article has an altmetric score of 170

Pathobiont-driven antibody sialylation through IL-10 undermines vaccination

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Abstract

The pathobiont Staphylococcus aureus (Sa) induces nonprotective antibody imprints that underlie ineffective staphylococcal vaccination. However, the mechanism by which Sa modifies antibody activity is not clear. Herein, we demonstrate that IL-10 is the decisive factor that abrogates antibody protection in mice. Sa-induced B10 cells drive antigen-specific vaccine suppression that affects both recalled and de novo developed B cells. Released IL-10 promotes STAT3 binding upstream of the gene encoding sialyltransferase ST3gal4 and increases its expression by B cells, leading to hyper-α2,3sialylation of antibodies and loss of protective activity. IL-10 enhances α2,3sialylation on cell-wall–associated IsdB, IsdA, and MntC antibodies along with suppression of the respective Sa vaccines. Consistent with mouse findings, human anti-Sa antibodies as well as anti-pseudomonal antibodies from cystic fibrosis subjects (high IL-10) are hypersialylated, compared with anti–Streptococcus pyogenes and pseudomonal antibodies from normal individuals. Overall, we demonstrate a pathobiont-centric mechanism that modulates antibody glycosylation through IL-10, leading to loss of staphylococcal vaccine efficacy.

Authors

Chih-Ming Tsai, Irshad A. Hajam, J.R. Caldera, Austin W.T. Chiang, Cesia Gonzalez, Xin Du, Biswa Choudhruy, Haining Li, Emi Suzuki, Fatemeh Askarian, Ty’Tianna Clark, Brian Lin, Igor H. Wierzbicki, Angelica M. Riestra, Douglas J. Conrad, David J. Gonzalez, Victor Nizet, Nathan E. Lewis, George Y. Liu

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Figure 4

IL-10 promotes STAT3 binding to St3gal4 promoter, which drives suppressive hypersialylation of IsdB antibodies.

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IL-10 promotes STAT3 binding to St3gal4 promoter, which drives suppressi...
(A) Number of putative STAT3 (IL-10) and NF-κB (IL-17A) binding sites on glycotransferase genes. (B) Effect of recombinant IL-10 on DNA-binding activity of STAT3 in naive splenic B cells, assessed by ChIP quantitative PCR (ChIP-qPCR) analysis. (C–F) Effect of αIL-10 antibody treatment on splenic B cell St3Gal (C), St6Gal (D), or Fut (E and F) expression. Experiment performed as in Figure 1D. (G) Effect of IsdB antibody desialylation on anti-Sa immunity in vivo. Naive mice were injected with α2-3 neuraminidase- or control- treated, purified Sa/IsdB antibody, then infected with LAC (n = 5 per mouse group). Bars represent group means; each point represents an individual mouse; error bars represent means ± SD (C–F). Bar represents group means; error bars represent means ± SD (B). Bar represents group median; each point represents an individual mouse; dashed lines indicate the limit of detection (G). *P < 0.05; **P < 0.01, 1-way ANOVA followed by Bonferroni’s multiple-comparison adjustment (C–G).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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