Symbionts exploit complex signaling to educate the immune system

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) ofBacteroides fragilisis 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.

Pairing Bacteroides vulgatus LPS Structure with Its Immunomodulatory Effects on Human Cellular Models

“… 52 − 54 Indeed, we firmly believe that the combination of all the peculiar chemical features of the LPS Bv molecule influences its net effect on human immune cells, and on this ground, the role of the Gal f unit in LPS Bv immunological properties is intriguing and requires a future in-depth study at the molecular level. In support of our hypothesis, a recent work by Erturk-Hasdemir et al (2019) 12 demonstrated that a covalently linked lipid anchor in polysaccharide A, the zwitterionic capsular polysaccharide of B. fragilis , was critical for the initiation of the anti-inflammatory immune response through the simultaneous activation of the TLR2 signaling (by the lipid anchor) and the Dectin-1 pathway (by the polysaccharide moiety). Similarly, we deem that the saccharide regions of LPS Bv heavily contribute and collaborate with the lipid A portion in dictating the innate immune signaling mechanisms leading to the activation of an anti-inflammatory response.…”

“… 10 Bacteroides surface structures have been shown to exert immunomodulatory effects. Examples are given by the capsular polysaccharide component from Bacteroides fragilis ( 11 , 12 ) but also the LPS from Bacteroides dorei that in a study by Vatanen et al was shown to promote immunological tolerance. 13 Recently, we demonstrated that Bacteroides vulgatus strain mpk, commensal of murine intestine, exerts strong immune-modulating properties leading to prevention of colitis-induction in several mouse models for experimental colitis.…”

Interaction between microbiota and immunity in health and disease

“…40 Polysaccharide A (PSA) produced by the commensal Bacteroides fragilis is another well-studied example of a single molecule promoting symbiosis and host immune system education. [57][58][59] PSA is recognized by the TLR2/TLR1 heterodimer in cooperation with Dectin-1 60 , a C-type lectin PRR. 61 Downstream to TLR1/TLR2 and Dectin-1 signaling, the phosphoinositide 3-kinase (PI3K) pathway is activated leading to inactivation of glycogen synthase kinase 3β (GSK3β), which in turn induces cAMP response elementbinding protein (CREB)-dependent expression of antiinflammatory genes.…”

“…61 Downstream to TLR1/TLR2 and Dectin-1 signaling, the phosphoinositide 3-kinase (PI3K) pathway is activated leading to inactivation of glycogen synthase kinase 3β (GSK3β), which in turn induces cAMP response elementbinding protein (CREB)-dependent expression of antiinflammatory genes. 60 Moreover, Dectin-1 may regulate intestinal immunity by controlling Treg cell differentiation through modification of microbiota configuration. 62 Additional PRRs suggested to shape the gut microbiota composition are NOD-like receptors (NLRs).…”

Age-Related Changes in the Gut Microbiota Promote Atrial Fibrillation

“…After proximal colon protein extraction, the protein solution was reduced with 5 mM dithiothreitol and 11 mM iodoacetamide for digestion [23]. The tryptic peptides were dissolved in proper sequence with 0.1% formic acid (solvent A) and different concentrations of solvent B (0.1% formic acid in 98% acetonitrile), followed by centrifugation with an EASY-nLC 1000 UPLC system.…”