IFN-I and CD8 T cells increase intestinal barrier permeability after chronic viral infection
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ABSTRACT:
PROVIDER: PRJNA648708 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12327063.fastq.gz | Fastqsanger.gz | |||
| SRR12327064.fastq.gz | Fastqsanger.gz | |||
| SRR12327065.fastq.gz | Fastqsanger.gz | |||
| SRR12327066.fastq.gz | Fastqsanger.gz | |||
| SRR12327067.fastq.gz | Fastqsanger.gz |
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Project description:Intestinal barrier leakage constitutes a potential therapeutic target for many inflammatory diseases and represents a disease progression marker during chronic viral infections. The causes of altered gut barrier remain, however, mostly unknown. By using murine infection with lymphocytic choriomeningitis virus we demonstrated that, in contrast to an acute viral strain, a persistent viral isolate led to long-term viral replication in hematopoietic and mesenchymal, but not epithelial (IEC), cells in the intestine. Viral persistence drove sustained intestinal epithelial barrier leakage, which was characterized by increased paracellular flux of small molecules and was associated with enhanced colitis susceptibility. IFN-I signaling caused tight junction dysregulation in IEC, promoted gut microbiome shifts and enhanced intestinal CD8 T cell responses. Notably, both IFN-I receptor blockade and CD8 T cell depletion prevented infection-induced barrier leakage. Our study demonstrated that infection with a virus that persistently replicated in intestinal mucosa increased epithelial barrier permeability, and revealed IFN-I and CD8 T cells as causative factors of intestinal leakage during chronic infections.
2020-08-26 | GSE155120 | GEO
Project description:Therapeutic treatment options for central nervous system diseases are greatly limited by the blood-brain barrier (BBB). Focused ultrasound (FUS), in conjunction with circulating microbubbles, can be used to induce a targeted and transient increase in BBB permeability, providing a unique approach for the delivery of drugs from the systemic circulation into the brain. While preclinical research has demonstrated the utility of FUS, there remains a large gap in our knowledge regarding the impact of sonication on BBB gene expression. This work is focused on investigating the transcriptional changes in dorsal hippocampal rat microvessels in the acute stages following sonication. Microarray analysis of microvessels was performed at 6 and 24 hrs post-FUS. Microvessels were collected by laser capture microdissection. Relative gene expression was compared between samples collected from the sonicated hemisphere and samples collected from the hemisphere contralateral to sonication, as well as samples collected from rats not undergoing the FUS procedure.
2017-09-01 | E-MTAB-5251 | biostudies-arrayexpress
Project description:Vitamin D receptor (VDR) is crucial for formation of epidermal permeability barrier and ceramide production, while mediator complex subunit 1 (Med1), a coactivator of VDR, mediates the action of VDR. VDR deficiency compromises epidermal permeability barrier in mice. Hence, we are investigating the dual role of VDR and Med1 in epidermal permeability barrier. Mice with VDR and Med1 specifically deleted in Keratin 14 expressing keratinocytes (DKO) by Cre-lox strategy are utilized. The mice with both floxed VDR and Med1 but no Cre serve as control. The data showed here that knockouts of both VDR and Med1 enhanced epidermal permeability barrier in mice, accompanied by increased expression levels of mRNA for keratinocyte differentiation marker-related proteins, fatty acid and ceramide productions, which all are required for formation of epidermal permeability barrier. Moreover, expression levels of mRNA for ceramide transporter (ABCA12) were also elevated in DKO mice vs. knockout of either VDR or Med1 alone. Collectively, these results demonstrate that knockouts of both VDR and Med1 enhance epidermal permeability barrier function via upregulating expression levels of mRNA for epidermal differentiation marker-related proteins and lipid synthetic enzymes, suggesting additional signaling pathway(s) involve regulatory role of VDR/Med1 in epidermal function.
2020-09-14 | GSE157887 | GEO
Project description:Although type III interferons (IFN), also known as IFN-λ or IL28/IL-29, restrict infection by several viruses, their mechanism of inhibitory action has remained uncertain. We used recombinant IFN-λ and mice lacking the IFN-λ receptor (IFNLR1) to evaluate the effect of IFN-λ on infection with West Nile virus (WNV), an encephalitic flavivirus. Cell culture studies in keratinocytes and dendritic cells showed no direct antiviral effect of exogenous IFN-λ even though ISGs were induced. Correspondingly, we observed no differences in WNV burden between wild-type and Ifnlr1-/- mice in the draining lymph node, spleen, and blood. However, we detected earlier dissemination and increased WNV infection in the brain and spinal cord of Ifnlr1-/- mice, yet this was not associated with a direct antiviral effect on infection of neurons. Instead, an increase in blood-brain barrier (BBB) permeability was observed in Ifnlr1-/- mice. Accordingly, treatment of mice with pegylated IFN-λ2 resulted in decreased BBB permeability, reduced WNV infection in the brain without impacting viremia, and improved survival against lethal virus challenge. An in vitro model of the BBB showed that IFN-λ signaling in brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and STAT1-independent manner. Our data establish a novel indirect antiviral function of IFN-λ in which non-canonical signaling through IFNLR1 tightens the BBB and restricts viral neuroinvasion and pathogenesis. This finding suggests new clinical applications for IFN-λ in treating viral or autoimmune diseases. Transcriptome profiling of bone-marrow derived Dendritic cells(BMDCs), treated with either Serum Free Media(Mock), interferon beta(IFNb), or interferon lambda(IFNL) for 6 hours.
2015-01-08 | E-GEOD-64735 | biostudies-arrayexpress
Project description:Rationale. The microvasculature of the central nervous system includes the blood-brain barrier (BBB), which regulates the permeability to nutrients and restricts the passage of toxic agents and inflammatory cells. Canonical Wnt/b-catenin signaling is responsible for the early phases of brain vascularization and blood-brain barrier differentiation. However, this signal declines after birth and other signaling pathways able to maintain barrier integrity at postnatal stage are still unknown. Objective. Sox17 constitutes a major downstream target of Wnt/b-catenin in endothelial cells and regulates arterial differentiation. In the present paper, we asked whether Sox17 may act downstream of Wnt/b-catenin in inducing BBB differentiation and maintenance. Methods and Results. Using reporter mice and nuclear staining of Sox17 and b-catenin, we report that while b-catenin signaling declines after birth, Sox17 activation increases and remains high in the adult. Endothelial-specific inactivation of Sox17 leads to increase of permeability of the brain microcirculation. The severity of this effect depends on the degree of BBB maturation: it is strong in the embryo, and progressively declines after birth. In search of Sox17 mechanism of action, RNA-Seq analysis of gene expression of brain endothelial cells has identified members of the Wnt/b-catenin signaling pathway as downstream targets of Sox17. Consistently, we found that Sox17 is a positive inducer of Wnt/b-catenin signaling and it acts in concert with this pathway to induce and maintain BBB properties. In vivo, inhibition of the b-catenin destruction complex or expression of a degradation-resistant b-catenin mutant, prevent the increase in permeability and retina vascular malformations observed in the absence of Sox17. Conclusions. Our data highlight a novel role for Sox17 in the induction and maintenance of the BBB and they underline the strict reciprocal tuning of this transcription factor and Wnt/b-catenin pathway. Modulation of Sox17 activity may be relevant to control BBB permeability in pathological conditions.
2019-02-12 | GSE122564 | GEO
Project description:The effect of neuronal activity on blood-brain barrier function and whether it plays a role in plasticity in the healthy brain remains unclear. We show that neuronal activity induces modulation of microvascular permeability in the healthy brain and that it has a role in local network reorganization. Combining simultaneous electrophysiological recording and vascular imaging with transcriptomic analysis in rats, and functional and BBB-mapping MRI in human subjects we show that prolonged stimulation of the limb induces a focal increase in BBB permeability in the corresponding somatosensory cortex that is associated with long-term synaptic plasticity. We further show that the increased microvascular permeability depends on neuronal activity and involves caveolae-mediated transcytosis and transforming growth factor beta signaling. Our results reveal a role of BBB modulation in cortical plasticity in the healthy brain, highlighting the importance of neurovascular interactions for sensory experience and learning.
2024-01-31 | GSE223282 | GEO
Project description:Intestinal barrier leakage constitutes a potential therapeutic target for many inflammatory diseases and represents a disease progression marker during chronic viral infections. However, the causes of altered gut barrier remain mostly unknown. Using murine infection with lymphocytic choriomeningitis virus, we demonstrate that, in contrast to an acute viral strain, a persistent viral isolate leads to long-term viral replication in hematopoietic and mesenchymal cells, but not epithelial cells (IECs), in the intestine. Viral persistence drove sustained intestinal epithelial barrier leakage, which was characterized by increased paracellular flux of small molecules and was associated with enhanced colitis susceptibility. Type I IFN signaling caused tight junction dysregulation in IECs, promoted gut microbiome shifts and enhanced intestinal CD8 T cell responses. Notably, both type I IFN receptor blockade and CD8 T cell depletion prevented infection-induced barrier leakage. Our study demonstrates that infection with a virus that persistently replicates in the intestinal mucosa increases epithelial barrier permeability and reveals type I IFNs and CD8 T cells as causative factors of intestinal leakage during chronic infections.
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Project description:In dorsal root ganglia (DRG), macrophages reside in close proximity to sensory neurons, and their functions have largely been explored in the context of pain, nerve injury and repair. In this study, however, we discovered that the majority of macrophages in DRGs are in direct contact with the vasculature where they constantly monitor the circulation, efficiently phagocytosing proteins and macromolecules from the blood. Characterization of the DRG endothelium revealed a specialized vascular network spanning the arteriovenous axis, which gradually transformed from a barrier type endothelium in arteries to a highly permeable endothelium in veins. Macrophage phagocytosis spatially aligned with peak endothelial permeability and we identified caveolar transcytosis as a mechanism regulating endothelial permeability. Profiling of the DRG immune landscape revealed two subsets of perivascular macrophages with distinct transcriptome, turnover and function. CD163 expressing macrophages self-maintained locally, specifically participated in vasculature monitoring, displayed distinct responses during peripheral inflammation and were conserved in mouse and Man. Our work provides a molecular explanation for the permeability of the blood-DRG barrier and identifies an unappreciated role of macrophages as integral components of the DRG-neurovascular unit. DOI: 10.1084/jem.20230675
2023-11-23 | GSE246168 | GEO
Project description:The role of astrocytes in innate immunity during viral infections of the central nervous system (CNS) remains to be fully elucidated. Here, we demonstrate that type I interferon (IFN) receptor (IFNAR) signaling in astrocytes regulates blood-brain barrier permeability and protects the cerebellum from infection and immunopathology. Mice with astrocytes lacking IFNAR signaling showed decreased survival after West Nile virus infection that was not due to expanded viral tropism or increased replication. Pattern recognition receptors and IFN-stimulated genes (ISGs) had higher basal and IFN-induced expression in human and mouse cerebellar astrocytes compared to cerebral cortical astrocytes. Our data identify cerebellar astrocytes as key responders to viral infection and highlight distinct innate immune programs in astrocytes from evolutionarily disparate regions of the CNS.
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