Bacteroides fragilis polysaccharide A induces IL-10 secreting B and T cells that prevent viral encephalitis
Abstract
The gut commensal Bacteroides fragilis or its capsular polysaccharide A (PSA) can prevent various peripheral and CNS sterile inflammatory disorders. Fatal herpes simplex encephalitis (HSE) results from immune pathology caused by uncontrolled invasion of the brainstem by inflammatory monocytes and neutrophils. Here we assess the immunomodulatory potential of PSA in HSE by infecting PSA or PBS treated 129S6 mice with HSV1, followed by delayed Acyclovir (ACV) treatment as often occurs in the clinical setting. Only PSA-treated mice survived, with dramatically reduced brainstem inflammation and altered cytokine and chemokine profiles. Importantly, PSA binding by B cells is essential for induction of regulatory CD4+ and CD8+ T cells secreting IL-10 to control innate inflammatory responses, consistent with the lack of PSA mediated protection in Rag−/−, B cell- and IL-10-deficient mice. Our data reveal the translational potential of PSA as an immunomodulatory symbiosis factor to orchestrate robust protective anti-inflammatory responses during viral infections.
Additional Information
© 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 14 September 2018; Accepted 02 April 2019; Published 14 May 2019. Data availability: All relevant data are available upon reasonable request. The source data underlying Figs. 1b, c, 2a–f, 3a–f, 4a–f, 5b, c, 6e and Supplementary Figs. 1a–f, 3e, 4a, b, 4d, 5c, 9a, e are provided in the Source Data file. We thank Dr. Andrew McKenzie, (MRC Laboratory of Molecular Biology, Cambridge, England) for providing BALB/c SIGNR1 KO and control wild type littermate mice. We thank Stacee Mendonca for excellent technical assistance. We thank Dr. Balfour Sartor (University of North Carolina) for providing the 129 IL-10KO spleen cells and Dr. Andrew Chan (Genentech Inc.) for providing anti CD20 monoclonal antibody. Portions of the graphics in Figs. 5 and 7 were obtained from Servier Medical Art, whom we gratefully acknowledge (http://smart.servier.com/). This study was funded by a grant from the Caltech-COH Biomedical Research Initiative to E.M.C. and S.K.M. and by a COH Shared Resources Pilot Program award to C.R. Author Contributions: E.M.C., S.K.M. and C.R. conceived the project and planned experiments, E.M.C. and S.K.M. provided reagents, H.C. purified PSA, C.R. performed experiments, M.K. isolated gut immune cells, L.L. labeled PSA with Alexa Fluor 488 and E.M.C. and C.R. wrote the paper. Competing interests: E.M.C., C.R. and S.K.M. are inventors of patent application: PCT/US2016/036803, which describes use of PSA as a treatment for viral inflammatory diseases. The remaining authors declare no competing interests.Attached Files
Published - s41467-019-09884-6.pdf
Supplemental Material - 41467_2019_9884_MOESM1_ESM.pdf
Supplemental Material - 41467_2019_9884_MOESM2_ESM.pdf
Supplemental Material - 41467_2019_9884_MOESM3_ESM.xlsx
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Additional details
- PMCID
- PMC6517419
- Eprint ID
- 95583
- Resolver ID
- CaltechAUTHORS:20190520-074644223
- Caltech-COH Biomedical Research Initiative
- City of Hope
- Created
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2019-05-20Created from EPrint's datestamp field
- Updated
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2022-02-25Created from EPrint's last_modified field