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  Symbionts exploit complex signaling to educate the immune system

Erturk-Hasdemir, D., Oh, S. F., Okan, N. A., Stefanetti, G., Gazzaniga, F. S., Seeberger, P. H., et al. (2019). Symbionts exploit complex signaling to educate the immune system. Proceedings of the National Academy of Sciences of the United States of America, 116(52), 26157-26166. doi:10.1073/pnas.1915978116.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-7F36-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-56B1-1
Genre: Journal Article

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 Creators:
Erturk-Hasdemir, Deniz, Author
Oh, Sungwhan F., Author
Okan, Nihal A., Author
Stefanetti, Giuseppe, Author
Gazzaniga, Francesca S., Author
Seeberger, Peter H.1, Author              
Plevy, Scott E., Author
Kasper, Dennis L., Author
Affiliations:
1Peter H. Seeberger - Vaccine Development, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_1863308              

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Free keywords: symbionts; Bacteroides fragilis; zwitterionic polysaccharied (ZPSs); polysaccharide A; host-microbe interactions
 Abstract: Human health and the microbiota are intricately intertwined. A major interest in manipulating the microbiome has been focused on the use of symbiont microbes to improve human health. However, relatively little has been discovered on the specific molecules from microbes in the microbiota that are immunomodulatory and the mechanisms by which these molecules regulate immunity. Herein we have defined how a symbiont molecule modulates innate immunity. Using polysaccharide A of Bacteroides fragilis as the paradigm for microbiome-induced immune responses, we have discovered important mechanisms by which symbiont molecules induce antiinflammatory responses. We reveal a lipid structure on polysaccharide A that drives host antiinflammatory responses by triggering a complex collaborative integration of Toll-like receptor, C-type lectin-like receptor, and PI3K signaling pathways.The mammalian immune system is tolerized to trillions of microbes residing on bodily surfaces and can discriminate between symbionts and pathogens despite their having related microbial structures. Mechanisms of innate immune activation and the subsequent signaling pathways used by symbionts to communicate with the adaptive immune system are poorly understood. Polysaccharide A (PSA) of Bacteroides fragilis is the model symbiotic immunomodulatory molecule. Here we demonstrate that PSA-dependent immunomodulation requires the Toll-like receptor (TLR) 2/1 heterodimer in cooperation with Dectin-1 to initiate signaling by the downstream phosphoinositide 3-kinase (PI3K) pathway, with consequent CREB-dependent transcription of antiinflammatory genes, including antigen presentation and cosignaling molecules. High-resolution LC-MS/MS analysis of PSA identified a previously unknown small molecular-weight, covalently attached bacterial outer membrane-associated lipid that is required for activation of antigen-presenting cells. This archetypical commensal microbial molecule initiates a complex collaborative integration of Toll-like receptor and C-type lectin-like receptor signaling mechanisms culminating in the activation of the antiinflammatory arm of the PI3K pathway that serves to educate CD4+ Tregs to produce the immunomodulatory cytokine IL-10. Immunomodulation is a key function of the microbiome and is a focal point for developing new therapeutic agents.

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Language(s): eng - English
 Dates: 2019-12-062019
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1073/pnas.1915978116
BibTex Citekey: Erturk-Hasdemir26157
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Title: Proceedings of the National Academy of Sciences of the United States of America
  Other : Proc. Acad. Sci. USA
  Other : Proc. Acad. Sci. U.S.A.
  Other : Proceedings of the National Academy of Sciences of the USA
  Abbreviation : PNAS
Source Genre: Journal
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Publ. Info: Washington, D.C. : National Academy of Sciences
Pages: - Volume / Issue: 116 (52) Sequence Number: - Start / End Page: 26157 - 26166 Identifier: ISSN: 0027-8424