Unknown,Transcriptomics,Genomics,Proteomics

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Membrane Vesicles of a Bacterial Mutualist Mediate Immune Regulation via Dendritic Cells

ABSTRACT: Microbial molecules have evolved to promote transient and/or permanent associations with mammals. Although numerous examples of secretion systems employed by pathogens have been described, mechanisms by which commensal bacteria export molecules during symbiosis remain unknown. The human gut mutualist Bacteroides fragilis produces a capsular polysaccharide (PSA) that directs host immune development. We reveal herein that outer membrane vesicles (OMVs) deliver PSA to dendritic cells (DCs), promoting regulatory T cells and inducing anti-inflammatory cytokines during protection from intestinal disease. In addition, we found that TLR2 signaling by DCs is required for OMV sensing. Following internalization into DCs and engagement of TLR2, OMVs initiate a gene expression program that results in IL-10 production by DCs. Although it is known that the outcome of PSA sensing by the immune system is Treg induction, nothing is known about the intracellular signaling pathway(s) activated by PSA within DCs. We analyzed the gene expression profile of DCs treated with OMVs to uncover factors that are expressed in a PSA-dependent, TLR2-dependent manner. Our findings demonstrate DC-induced protection from disease via OMV-delivery of a beneficial microbial molecule, uncovering a novel paradigm for inter-kingdom communication between the microbiota and mammals. RNA samples (1ug total RNA) from BMDCs were labeled with fluorescent dyes using the Quick Amp Labeling Kit (Agilent). Microarray (AgilentWhole Mouse Genome chip) hybridizations (65M-BM-0C for 16 hours) and washes were performed with Agilent reagents following standard protocols. Microarrays were analyzed using an Agilent DNA Microarray Scanner G2565CA, and data were acquired using Agilent's Feature Extraction Software version 10.1.1.1. Significant genes were selected based on p< 0.01 and fold change >2.0.

ORGANISM(S): Mus musculus

SUBMITTER: Yue Shen

PROVIDER: E-GEOD-39563 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Individual genetic variation affects gene expression and cell phenotype by acting within complex molecular circuits, but this relationship is still largely unknown. Here, we combine genomic and meso-scale profiling with novel computational methods to detect genetic variants that affect the responsiveness of gene expression to stimulus (responsiveness QTLs) and position them in circuit diagrams. We apply this approach to study individual variation in transcriptional responsiveness to three different pathogen components in the model response of primary bone marrow dendritic cells (DCs) from recombinant inbred mice strains. We show that reQTLs are common both in cis (affecting a single target gene) and in trans (pleiotropically affecting co-regulated gene modules) and are specific to some stimuli but not others. Leveraging the stimulus-specific activity of reQTLs and the differential responsiveness of their associated targets, we show how to position reQTLs within the context of known pathways in this regulatory circuit. For example, we find that a pleiotropic trans-acting genetic factor in chr1:129-165Mb affects the responsiveness of 35 anti-viral genes only during an anti-viral like stimulus. Using RNAi we uncover RGS16 the likely causal gene in this interval, and an activator of the antiviral response. Our approach charts an experimental and analytic path to decipher the mechanisms underlying genetic variation in other complex circuits in primary mammalian cells. The transcriptional response of DCs to pathogen components in the context of the mouse BXD recombinant inbred lines. We isolated DCs from individual age-synchronized female mice of different BXD and parental strains. We measured 30 global transcription profiles in resting and stimulated DCs from two parental strains (B6 and D2) and six BXD strains. We used bone marrow derived primary DCs from a panel of recombinant inbred (RI) BXD mice derived from a cross of the parental C57BL/6J (B6) and DBA/2J (D2) strains. We measured transcriptional responses in DCs from each of two parental strains and 6 BXD strains stimulated by three ligands of Toll-like receptors: LPS (TLR4 ligand), Pam3CSK ('PAM', TLR2 ligand) and poly IC (TLR3/RIG-I ligand).

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Membrane Vesicles of a Bacterial Mutualist Mediate Immune Regulation via Dendritic Cells

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