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Symbionts Exploit Complex Signaling to Educate the Immune System

55 Pages Posted: 1 Apr 2019 Sneak Peek Status: Review Complete

See all articles by Deniz Erturk-Hasdemir

Deniz Erturk-Hasdemir

Harvard Medical School - Division of Immunology

Sungwhan F. Oh

Harvard University - Center for Experimental Therapeutics and Reperfusion Injury

Nihal A. Okan

Harvard Medical School - Division of Immunology

Giuseppe Stefanetti

Harvard Medical School - Division of Immunology

Francesca Gazzaniga

Harvard Medical School - Division of Immunology

Peter Seeberger

Max Planck Institute of Colloids and Interfaces - Department of Biomolecular Systems

Scott E. Plevy

Janssen Research & Development, LLC

Dennis L. Kasper

Harvard Medical School - Division of Immunology

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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 TLR2/TLR1 heterodimer in cooperation with Dectin-1 to initiate signaling by the downstream PI3K pathway, with consequent CREB-dependent transcription of anti-inflammatory genes including antigen presentation and co-signaling 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 TLR and C-type lectin–like receptor signaling mechanisms culminating in the activation of the anti-inflammatory arm of the PI3K pathway that serves to educate CD4+ Tregs to produce the immunomodulatory cytokine interleukin 10. Immunomodulation is a key function of the microbiome and is a focal point for developing new therapeutic agents.

Keywords: symbionts, Bacteroides fragilis, zwitterionic polysaccharides (ZPSs), Polysaccharide A, immunomodulation, innate immune signaling, host‐microbe interactions

Suggested Citation

Erturk-Hasdemir, Deniz and Oh, Sungwhan F. and Okan, Nihal A. and Stefanetti, Giuseppe and Gazzaniga, Francesca and Seeberger, Peter and Plevy, Scott E. and Kasper, Dennis L., Symbionts Exploit Complex Signaling to Educate the Immune System (March 30, 2019). Available at SSRN: https://ssrn.com/abstract=3362573 or http://dx.doi.org/10.2139/ssrn.3362573
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Deniz Erturk-Hasdemir

Harvard Medical School - Division of Immunology

25 Shattuck St
Boston, MA 02115
United States

Sungwhan F. Oh

Harvard University - Center for Experimental Therapeutics and Reperfusion Injury

75 Francis St.
Boston, MA 02115
United States

Nihal A. Okan

Harvard Medical School - Division of Immunology

25 Shattuck St
Boston, MA 02115
United States

Giuseppe Stefanetti

Harvard Medical School - Division of Immunology

25 Shattuck St
Boston, MA 02115
United States

Francesca Gazzaniga

Harvard Medical School - Division of Immunology

25 Shattuck St
Boston, MA 02115
United States

Peter Seeberger

Max Planck Institute of Colloids and Interfaces - Department of Biomolecular Systems

Potsdam-Golm Science Park
Potsdam, 14476
Germany

Scott E. Plevy

Janssen Research & Development, LLC

United States

Dennis L. Kasper (Contact Author)

Harvard Medical School - Division of Immunology ( email )

25 Shattuck St
Boston, MA 02115
United States

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