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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) 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.

SUBMITTER: Erturk-Hasdemir D

PROVIDER: S-EPMC6936714 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Symbionts exploit complex signaling to educate the immune system.

Erturk-Hasdemir Deniz D Oh Sungwhan F SF Okan Nihal A NA Stefanetti Giuseppe G Gazzaniga Francesca S FS Seeberger Peter H PH Plevy Scott E SE Kasper Dennis L DL

Proceedings of the National Academy of Sciences of the United States of America 20191206 52

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 <i>Bacteroides fragilis</i> is the model symbiotic immunomodulatory molecule. Here we demonstrate that PSA-depe ...[more]

PMID: 31811024

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Project description:Beneficial microbial symbionts serve important functions within their hosts, including dietary supplementation and maintenance of immune system homeostasis. Little is known about the mechanisms that enable these bacteria to induce specific host phenotypes during development and into adulthood. Here we used the tsetse fly, Glossina morsitans, and its obligate mutualist, Wigglesworthia glossinidia, to investigate the co-evolutionary adaptations that influence the development of host physiological processes. Wigglesworthia is maternally transmitted to tsetse's intrauterine larvae through milk gland secretions. We can produce flies that lack Wigglesworthia (Gmm(Wgm-) yet retain their other symbiotic microbes. Such offspring give rise to adults that exhibit a largely normal phenotype, with the exception being that they are reproductively sterile. Our results indicate that when reared under normal environmental conditions Gmm(Wgm-) adults are also immuno-compromised and highly susceptible to hemocoelic E. coli infections while age-matched wild-type individuals are refractory. Adults that lack Wigglesworthia during larval development exhibit exceptionally compromised cellular and humoral immune responses following microbial challenge, including reduced expression of genes that encode antimicrobial peptides (cecropin and attacin), hemocyte-mediated processes (thioester-containing proteins 2 and 4 and prophenoloxidase), and signal-mediating molecules (inducible nitric oxide synthase). Furthermore, Gmm(Wgm-) adults harbor a reduced population of sessile and circulating hemocytes, a phenomenon that likely results from a significant decrease in larval expression of serpent and lozenge, both of which are associated with the process of early hemocyte differentiation. Our results demonstrate that Wigglesworthia must be present during the development of immature progeny in order for the immune system to function properly in adult tsetse. This phenomenon provides evidence of yet another important physiological adaptation that further anchors the obligate symbiosis between tsetse and Wigglesworthia.

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Symbionts exploit complex signaling to educate the immune system.

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Symbionts exploit complex signaling to educate the immune system.

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