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

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

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Figure 2

B10 cells abrogate humoral protection induced by IsdB vaccination.

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B10 cells abrogate humoral protection induced by IsdB vaccination. (A) I...
(A) IL-10 in culture supernatant 16 hours after stimulation of naive or Sa-experienced splenic B cells with LPS or heat-killed Sa at indicated MOI.NT, nontreated. (B) αIL-10 antibody abrogates suppressive B cell effect on IsdB vaccination. Naive mice administered B cells from Sa-exposed mice were IsdB vaccinated with/without αIL-10 antibody, then challenged as per Figure 1A (n = 4–5 per mouse group). (C) αCD22 antibody depletion of B10 cells a day prior to immunizations restores IsdB vaccine efficacy. (n = 7–10 per mouse group from 3 independent experiments). (D) Experimental setup for E and F. Splenic B cells were transferred from naive/Sa-infected CD45.1 mice into naive CD45.2 mice. Recipients were IsdB immunized, and splenic B cells were analyzed after 7 days (E). CD45.1 or CD45.2 B cells were then transferred into naive C57BL/6 mice followed by Sa challenge (F). (E) No difference in percentage (F) but lack of protective function of de novo developed (CD45.2) splenic B cells in mice exposed to suppressive B cells. (E and F) CD45.1, n = 5 per group, CD45.2, n = 20 per group from 4 independent experiments. (G) Bacterial burden in WT CD19cre/+ mice or CD19cre/+ IL-10RAfl/fl that were infected and IsdB vaccinated as per Figure 1A (n = 8–10 per mouse group from 3 independent experiments). (H) B cells do not suppress IsdB vaccination when IsdB/HarA mutant Becker strain is used in prior infection. Infection/vaccination as per Figure 1A followed by antibody transfer. WT Becker was used in final challenge. (n = 15 per mouse group from 3 independent experiments). Bars represent group means; error bars represent means ± SD (A). Dashed lines indicate the limit of detection (B to C and E to H). *P < 0.05; ***P < 0.001; ****P < 0.0001, 1-way ANOVA followed by Bonferroni’s multiple-comparison adjustment (A to C and E to H).