Recent studies using culture-independent methods have characterized the human airway microbiota and report microbial communities distinct from other body sites. Changes in these airway bacterial communities appear to be associated with inflammatory lung disease, yet the pro-inflammatory properties of individual bacterial species are unknown. In this study, we compared the immune stimulatory capacity on human monocyte-derived dendritic cells (DCs) of selected airway commensal and pathogenic bacteria predominantly associated with lungs of asthma or COPD patients (pathogenic Haemophillus spp. and Moraxella spp.), healthy lungs (commensal Prevotella spp.) or both (commensal Veillonella spp. and Actinomyces spp.). All bacteria were found to induce activation of DCs as demonstrated by similar induction of CD83, CD40 and CD86 surface expression. However, asthma and COPD-associated pathogenic bacteria provoked a 3–5 fold higher production of IL-23, IL-12p70 and IL-10 cytokines compared to the commensal bacteria. Based on the differential cytokine production profiles, the studied airway bacteria could be segregated into three groups (Haemophilus spp. and Moraxella spp. vs. Prevotella spp. and Veillonella spp. vs. Actinomyces spp.) reflecting their pro-inflammatory effects on DCs. Co-culture experiments found that Prevotella spp. were able to reduce Haemophillus influenzae-induced IL-12p70 in DCs, whereas no effect was observed on IL-23 and IL-10 production. This study demonstrates intrinsic differences in DC stimulating properties of bacteria associated with the airway microbiota.
Summary Steroid hormones control important developmental processes and are linked to many diseases. To systematically identify genes and pathways required for steroid production, we performed a Drosophila genome-wide in vivo RNAi screen and identified 1,906 genes with potential roles in steroidogenesis and developmental timing. Here, we use our screen as a resource to identify mechanisms regulating intracellular levels of cholesterol, a substrate for steroidogenesis. We identify a conserved fatty acid elongase that underlies a mechanism which adjusts cholesterol trafficking and steroidogenesis with nutrition and developmental programs. Additionally, we demonstrate the existence of an autophagosomal cholesterol mobilization mechanism and show that activation of this system rescues Niemann Pick type C1-deficiency that causes a disorder characterized by cholesterol accumulation. These cholesterol trafficking mechanisms are regulated by TOR and feedback signaling that couples steroidogenesis with growth and ensure proper maturation timing. These results reveal genes regulating steroidogenesis during development that likely modulate disease mechanisms.
The inflammatory intestinal disorder Crohn's disease (CD) has become a health challenge worldwide. The gut microbiota closely interacts with the host immune system, but its functional impact in CD is unclear. Except for studies on a small number of CD patients, analyses of the gut microbiota in CD have used 16S rDNA amplicon sequencing. Here we employed metagenomic shotgun sequencing to provide a detailed characterization of the compositional and functional features of the CD microbiota, comprising also unannotated bacteria, and investigated its modulation by exclusive enteral nutrition. Based on signature taxa, CD microbiotas clustered into 2 distinct metacommunities, indicating individual variability in CD microbiome structure. Metacommunity-specific functional shifts in CD showed enrichment in producers of the pro-inflammatory hexa-acylated lipopolysaccharide variant and a reduction in the potential to synthesize short-chain fatty acids. Disruption of ecological networks was evident in CD, coupled with reduction in growth rates of many bacterial species. Short-term exclusive enteral nutrition elicited limited impact on the overall composition of the CD microbiota, although functional changes occurred following treatment. The microbiotas in CD patients can be stratified into 2 distinct metacommunities, with the most severely perturbed metacommunity exhibiting functional potentials that deviate markedly from that of the healthy individuals, with possible implication in relation to CD pathogenesis.
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The capacity to develop protective immunity against mycobacteria is heterogeneously distributed among human beings, and it is currently unknown why the initial immune response induced against Mycobacterium tuberculosis (Mtb) does not provide proper clearance of this pathogen. Dendritic cells (DCs) are some of the first cells to interact with Mtb and they play an essential role in development of protective immunity against Mtb. Given that Mtb-infected macrophages have difficulties in degrading Mtb, they need help from IFN-γ-producing CD4+ T cells propagated via IL-12p70-producing DCs. Here we report that Mtb modifies human DC plasticity by expanding a CD14+ DC subset with weak IL-12p70-producing capacity. The CD14+ Mtb-promoted subset was furthermore poor inducers of IFN-γ by naive CD4+ T cells, but instead prompted IL-17A-producing RORγT+ CD4+ T cells. Mtb-derived peptidoglycan and mannosylated lipoarabinomannan partly recapitulated the subset partition induced by Mtb. Addition of IFN-γ, but neither IL-17A nor IL-22, which are potentially produced by Mtb-exposed γ/δ-T cells in mucosal linings, inhibited the differentiation toward CD14+ DCs and promoted high-level IL-12p70 in Mtb-challenged DCs. We conclude that Mtb exploits DC plasticity to reduce production of IL-12p70, and that this process is entirely divertible by exogenous IFN-γ. These data suggest that strategies to increase local IFN-γ production in the lungs of tuberculosis patients may boost host immunity toward Mtb.
Cancer immunotherapy is a powerful new tool in the oncologist's therapeutic arsenal, with our increased knowledge of anti-tumor immunity providing many new targets for intervention. Monocytes and dendritic cells (DCs) are attractive targets for enhancing the anti-tumor immune response, but systemic delivery of immunomodulators has proven to be associated with a high risk of fatal adverse events due to the systemic activation of the immune system. We address this important obstacle by targeting the delivery of an immunomodulator, a Toll-like receptor agonist, to DCs and monocytes in the bloodstream. We thus focus the activation, potentially avoiding the above-mentioned adverse effects, and demonstrate greatly increased ability of the agonist to induce secretion of anti-cancer cytokines.
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