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.
View: Text | PDF
Research Article Immunology Infectious disease

Pathobiont-driven antibody sialylation through IL-10 undermines vaccination

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

×

Figure 6

Hyper-α2,3 sialylation of human anti-Sa antibodies.

Options: View larger image (or click on image) Download as PowerPoint
Hyper-α2,3 sialylation of human anti-Sa antibodies. (A and B) α-2,6 and ...
(A and B) α-2,6 and α-2,3 sialylation of purified human serum Sa antibodies (n = 9) as assessed by SNA and MAA lectin binding normalized to IgG titer. (C) Sialylation of purified human serum antibodies against M protein (M) or S protein (S) of Streptococcus pyogenes (n = 18) as assessed by MAA and SNA lectin binding normalized to IgG titer. Gray dashed line indicates median SNA or MAA level of IsdB antibody. (D) Sialylation of purified human serum antibodies against P. aeruginosa CbpD or FliC (n = 5) as assessed by MAA and SNA lectin binding normalized to IgG titer. H, healthy normal human; CF, subject with cystic fibrosis. Gray dashed line indicates median SNA or MAA level of IsdB antibody. (E) OPK of Sa (LAC) by primary mouse neutrophils in the presence of human IsdB antibodies treated with α2-3 neuraminidase or buffer control from human donors (n = 9). (F) Correlation between purified human serum IsdB antibody (n = 9) binding to MAA lectin and OPK of LAC. Green circle indicates IsdB antibodies treated with α-2,3 neuraminidase. Bars represent group median; each point represents an individual human donor; error bars represent means± SD (A–D). Each point represents an individual human donor (E and F). *P < 0.05; **P < 0.01; ***P < 0.001, Student’s t test (C–E), 1-way ANOVA followed by Bonferroni’s multiple-comparison adjustment (A and B) or linear regression (F).