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Symbionts exploit complex signaling to educate the immune system.

Deniz Erturk-Hasdemir1, Sungwhan F Oh1,2, Nihal A Okan1,3

  • 1Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115.

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Polysaccharide A (PSA) from Bacteroides fragilis modulates the immune system by activating Toll-like receptor 2/1 and Dectin-1. This promotes anti-inflammatory responses and educates regulatory T cells (Tregs).

Keywords:
Bacteroides fragilishost–microbe interactionspolysaccharide Asymbiontszwitterionic polysaccharides (ZPSs)

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Area of Science:

  • Immunology
  • Microbiology
  • Molecular Biology

Background:

  • Mammalian immune systems tolerate commensal microbes but can distinguish them from pathogens.
  • Mechanisms of innate immune activation by symbionts and their communication with the adaptive immune system are not fully understood.
  • Polysaccharide A (PSA) from Bacteroides fragilis is a key molecule in symbiotic immune modulation.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which PSA modulates the immune system.
  • To identify the specific receptors and signaling pathways involved in PSA-mediated immune tolerance.
  • To understand how commensal bacteria educate the immune system for maintaining homeostasis.

Main Methods:

  • Utilized Toll-like receptor (TLR) 2/1 heterodimer and Dectin-1 signaling pathways.
  • Investigated the downstream phosphoinositide 3-kinase (PI3K) pathway and CREB-dependent transcription.
  • Employed high-resolution LC-MS/MS analysis to identify molecular components of PSA.
  • Assessed the activation of antigen-presenting cells and CD4+ regulatory T cells (Tregs).

Main Results:

  • PSA-dependent immunomodulation requires the TLR 2/1 heterodimer and Dectin-1.
  • Signaling converges on the PI3K pathway, leading to CREB-dependent transcription of anti-inflammatory genes.
  • A novel bacterial outer membrane-associated lipid, essential for PSA's function, was identified.
  • PSA activates antigen-presenting cells and educates CD4+ Tregs to produce IL-10.

Conclusions:

  • Commensal microbial molecules like PSA engage complex TLR and C-type lectin-like receptor signaling.
  • This interaction activates the anti-inflammatory arm of the PI3K pathway, crucial for immune homeostasis.
  • Understanding these mechanisms is vital for developing microbiome-based therapeutic strategies.