Symbionts exploit complex signaling to educate the immune system
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 comm...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 52; pp. 26157 - 26166 |
|---|---|
| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
26.12.2019
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| Series | Inaugural Article |
| Subjects | |
| Online Access | Get full text |
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| Abstract | 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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| AbstractList | 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
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. 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. 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. |
| Author | Erturk-Hasdemir, Deniz Plevy, Scott E. Okan, Nihal A. Oh, Sungwhan F. Gazzaniga, Francesca S. Stefanetti, Giuseppe Kasper, Dennis L. Seeberger, Peter H. |
| Author_xml | – sequence: 1 givenname: Deniz surname: Erturk-Hasdemir fullname: Erturk-Hasdemir, Deniz – sequence: 2 givenname: Sungwhan F. surname: Oh fullname: Oh, Sungwhan F. – sequence: 3 givenname: Nihal A. surname: Okan fullname: Okan, Nihal A. – sequence: 4 givenname: Giuseppe surname: Stefanetti fullname: Stefanetti, Giuseppe – sequence: 5 givenname: Francesca S. surname: Gazzaniga fullname: Gazzaniga, Francesca S. – sequence: 6 givenname: Peter H. surname: Seeberger fullname: Seeberger, Peter H. – sequence: 7 givenname: Scott E. surname: Plevy fullname: Plevy, Scott E. – sequence: 8 givenname: Dennis L. surname: Kasper fullname: Kasper, Dennis L. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31811024$$D View this record in MEDLINE/PubMed |
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| Keywords | host–microbe interactions Bacteroides fragilis symbionts polysaccharide A zwitterionic polysaccharides (ZPSs) |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: D.E.-H., S.F.O., G.S., F.S.G., and D.L.K. designed research; D.E.-H., S.F.O., N.A.O., and G.S. performed research; D.E.-H., S.F.O., P.H.S., and S.E.P. contributed new reagents/analytic tools; D.E.-H., S.F.O., N.A.O., and G.S. analyzed data; and D.E.-H., S.F.O., and D.L.K. wrote the paper. Contributed by Dennis L. Kasper, November 4, 2019 (sent for review September 15, 2019; reviewed by Robert W. Finberg and Lora V. Hooper) Reviewers: R.W.F., University of Massachusetts Medical School; and L.V.H., University of Texas Southwestern Medical Center. This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2018. 1Present address: Synlogic Therapeutics, Cambridge, MA 02142. |
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| Snippet | The mammalian immune system is tolerized to trillions of microbes residing on bodily surfaces and can discriminate between symbionts and pathogens despite... Human health and the microbiota are intricately intertwined. A major interest in manipulating the microbiome has been focused on the use of symbiont microbes... |
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| Title | Symbionts exploit complex signaling to educate the immune system |
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