Metabolic Deficiencies Underlie Reduced Plasmacytoid Dendritic Cell IFN-I Production following Viral Infection
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PROVIDER: PRJNA1206695 | ENA |
REPOSITORIES: ENA
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Project description:Metabolic Deficiencies Underlie Reduced Plasmacytoid Dendritic Cell IFN-I Production following Viral Infection [RNA-Seq]
| PRJNA1202098 | ENA
Project description:Type I Inter ferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their exceptional IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition.
2025-01-05 | GSE285874 | GEO
Project description:T ype I Inter ferons (IFN-I) are central to host protection against viral infections, with plasmacytoid de ndritic cells (pDC) being the most significant source, yet pDCs lose their exceptional IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition.
2025-01-05 | GSE285244 | GEO
Project description: Not available
| S-EPMC11805920 | biostudies-literature
Project description:Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid dendritic cells (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A. fumigatus infection and the molecular events that underlie the protective pDC - neutrophil crosstalk. Fungus-induced pDC activation begins after bone marrow egress and results in pDC-dependent regulation of lung type I and type III IFN levels. These pDC-derived products act on type I and type III IFN receptor-expressing neutrophils and control neutrophil fungicidal activity and reactive oxygen species production via STAT1 signaling in a cell-intrinsic manner. Mechanistically, neutrophil STAT1 signaling regulates the transcription and expression of Cybb, which encodes one of five NADPH oxidase subunits. Thus, pDCs regulate sterilizing immunity against inhaled molds by controlling the local expression of a subunit required for functional NADPH oxidase assembly and activity in the lung.
2025-07-17 | GSE280229 | GEO
Project description:Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid dendritic cells (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A. fumigatus infection and the molecular events that underlie the protective pDC - neutrophil crosstalk. Fungus-induced pDC activation begins after bone marrow egress and results in pDC-dependent regulation of lung type I and type III IFN levels. These pDC-derived products act on type I and type III IFN receptor-expressing neutrophils and control neutrophil fungicidal activity and reactive oxygen species production via STAT1 signaling in a cell-intrinsic manner. Mechanistically, neutrophil STAT1 signaling regulates the transcription and expression of Cybb, which encodes one of five NADPH oxidase subunits. Thus, pDCs regulate sterilizing immunity against inhaled molds by controlling the local expression of a subunit required for functional NADPH oxidase assembly and activity in the lung.
2025-07-17 | GSE280164 | GEO
Project description:Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid dendritic cells (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A. fumigatus infection and the molecular events that underlie the protective pDC - neutrophil crosstalk. Fungus-induced pDC activation begins after bone marrow egress and results in pDC-dependent regulation of lung type I and type III IFN levels. These pDC-derived products act on type I and type III IFN receptor-expressing neutrophils and control neutrophil fungicidal activity and reactive oxygen species production via STAT1 signaling in a cell-intrinsic manner. Mechanistically, neutrophil STAT1 signaling regulates the transcription and expression of Cybb, which encodes one of five NADPH oxidase subunits. Thus, pDCs regulate sterilizing immunity against inhaled molds by controlling the local expression of a subunit required for functional NADPH oxidase assembly and activity in the lung.
2025-07-29 | GSE303828 | GEO
Project description:we report that free cholesterol in the endolysosomal membrane regulates the IFN-I response in plasmacytoid dendritic cells (pDCs) by facilitating the release of TLR9 from UNC93B1.
| PXD051868 |
Project description:Type I interferons (IFN-I) are important mediators of antiviral immunity and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) from females exert an elevated capacity to produce IFN-I in response to activation of toll-like receptor 7 (TLR7) compared to male pDCs, and both hormones and genes encoded by the X chromosome have been implicated in these sex-specific differences. Using longitudinal samples collected from a cohort of trans men receiving testosterone injections as gender-affirming hormone therapy (GAHT), the impact of testosterone on TLR7-mediated IFN-I production by pDCs was assessed. GAHT induced testosterone and estradiol levels within male reference ranges and increased hemoglobin and hematocrit levels, demonstrating biological activity of testosterone. scRNA seq of pDCs showed downregulation of IFN-I-related gene expression signatures, but also revealed inter-donor heterogeneity on the transcriptional level. Longitudinal quantification of IFN-I protein production by pDCs following TLR7-stimulation showed significant and continuous reduction of IFN-I production in trans men, and reduced expression of IFN-I-stimulated genes. These longitudinal studies in trans men demonstrate that testosterone can reduce IFN-I production by pDCs, and provide novel insights into the immune-modulatory role of testosterone in sex differential IFN-I-mediated immune responses.
2023-11-09 | GSE231370 | GEO
Project description:Multiple Sclerosis (MS) is an immune-mediated chronic inflammatory disease affecting the central nervous system. The cause of MS is not known and the mechanism of IFN-beta, a disease-modifying treatment (DMT) approved for MS, is not well-understood. Oligonucleotide microarrays were used to study gene expression in plasmacytoid denditic cells (pDCs) which are antigen-presenting cells implicated in MS pathogenesis. We analyzed gene expression in pDCs of healthy controls, untreated and IFN-beta treated MS patients. We were able to identify 60 genes which were abnormally expressed in untreated MS patients and were corrected after treatment with IFN-beta. PDCs were separated from healthy donors and MS patients at two time points: before and 3 months after initiation of treatment with IFN-beta for RNA extraction and hybridization on Affymetrix microarrays. Gene expression data analysis of was done by GeneSpring software (Agilent Technologies). An unpaired t-test was applied to select genes with significant difference in expression between healthy donors and untreated MS patients. A paired t-test was applied to select genes with significant difference in expression in MS patients before and after IFN-beta treatment. To select differentially expressed/regulated genes, the cut-off criteria consisted of a P value < 0.05 and fold change >1.5.
2015-05-02 | E-GEOD-37750 | biostudies-arrayexpress