Aryl hydrocarbon receptor senses bacterial pigmented virulence factors and orchestrates anti-bacterial defenses
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Hans-Joachim Mollenkopf
PROVIDER: E-GEOD-48133 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The aryl hydrocarbon receptor (AhR) is a highly conserved ligand-dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses. We hypothesized that AhR not only evolved to sense pollutants from the environment, but also insults of microbial origin. We demonstrate that bacterial pigmented virulence factors, namely the phenazines pyocyanin and 1-hydroxyphenazine from Pseudomonas aeruginosa and the naphthoquinone phthiocol from Mycobacterium tuberculosis, are ligands of AhR. AhR activation leads to degradation of these virulence factors and regulated cytokine and chemokine production. The relevance of AhR to host defense is underlined by heightened susceptibility of AhR-deficient mice, both to P. aeruginosa and M. tuberculosis. Our data demonstrate that AhR senses distinct bacterial virulence factors and controls anti-bacterial responses. We provide evidence for a previously unidentified role for AhR as an intracellular pattern recognition receptor, and identify bacterial pigmented virulence factors as a new class of pathogen-associated molecular patterns. Microarray experiments were performed as dual-color hybridizations. To compensate for dye-specific effects, a dye-reversal color-swap was applied. Quality control and quantification of total RNA amount was assessed using an Agilent 2100 Bioanalyzer (Agilent Technologies) and a NanoDrop 1000 spectrophotometer (Kisker).
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Project description:The activity of the potent nasal adjuvant flagellin depends on initial activation of airway epithelilal cells. This study aims at investigating the immune cells involved in the antigen presentation within the respiratory tract. First, microarrays characterized that activation/recruitment of immune cells was the main signature of flagellin activation in lung. Neutrophils and classical monocytes were strongly recruited into the lungs and take up antigen upon nasal administration of flagellin. In contrast, the numbers of lung CD11b+ or CD103+ DC and alveolar macrophages were not enhanced although these cells were very efficient in antigen uptake. Our experiments showed that CD11b+ DC but not monocytes, PMN, CD103+ DC are not essential for the adjuvant effect. Flagellin signaling enhanced the functional activation of lung CD11b+ conventional DC and their migration to the lymph nodes. Using Cd11c-DTR mice, CD11b+ DC from lymph nodes were identified as the major stimulators of CD4 T cell activation. Finally, the migration and maturation of mucosal DC was independent of direct signaling, highlighting the contribution of epithelial factors in the mucosal adjuvant effect of flagellin. In conclusion, these data demonstrate that adjuvant activity can be dissociated from inflammatory cell recruitment an open new perpectives for improvement of vaccines. Female C57BL/6J (6 weeks old) mice were immunized with the TLR5 agonist Flagellin (1μg diluted in PBS) by intranasal (i.n.) administration. Blood samples of four time points post immunization were taken at 2h, 4h, 18h and 48h. Microarray experiments were performed as single-color hybridizations.
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Project description:The aryl hydrocarbon receptor (AhR) is a highly conserved ligand-dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses. We hypothesized that AhR not only evolved to sense pollutants from the environment, but also insults of microbial origin. We demonstrate that bacterial pigmented virulence factors, namely the phenazines pyocyanin and 1-hydroxyphenazine from Pseudomonas aeruginosa and the naphthoquinone phthiocol from Mycobacterium tuberculosis, are ligands of AhR. AhR activation leads to degradation of these virulence factors and regulated cytokine and chemokine production. The relevance of AhR to host defense is underlined by heightened susceptibility of AhR-deficient mice, both to P. aeruginosa and M. tuberculosis. Our data demonstrate that AhR senses distinct bacterial virulence factors and controls anti-bacterial responses. We provide evidence for a previously unidentified role for AhR as an intracellular pattern recognition receptor, and identify bacterial pigmented virulence factors as a new class of pathogen-associated molecular patterns. Microarray experiments were performed as single-color hybridizations. Quality control and quantification of total RNA amount was assessed using an Agilent 2100 Bioanalyzer (Agilent Technologies) and a NanoDrop 1000 spectrophotometer (Kisker).
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Project description:Global transcriptome analyses provide an excellent basis for the identification and definition of biomarkers with high relevance in infection processes, therapeutic intervention and protective immunity. The measurement applies three different state of the art transcriptomic technologies for global expression profiling to vaccine development. Different microarray platforms in conjunct to next generation sequencing (NGS) will build the basis for comparative approaches, such as up-down classification and correlation coefficients. This measurement is based on Agilent microarrays and a clinical trial phase Ib study with M. bovis BCG vaccination. M-bM-^@M-" Surrogate measurement using whole human blood M-bM-^@M-" 4 time points: d0 (naM-CM-/ve, pre-immunization) and d14, d28,d56, d168 post m. bovis BCG immunization M-bM-^@M-" Responses of PPD positive study groups M-bM-^@M-" Group size of approximately 6 individuals European network of vaccine research and development (TRANSVAC) Microarray experiments were performed as single-color hybridizations using Agilent Technologies whole human genome 4x44K microarrays
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