Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA315809 | ENA |
REPOSITORIES: ENA
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Project description:West Nile virus (WNV) is the most important cause of endemic encephalitis in the USA. Strikingly, only a small percentage of patients develop clinical disease and of these patients, approximately 1 out of 150 patients develops encephalitis. The basis for this great variability in disease outcome is unknown, but may be related to the innate immune response. Innate immune responses, critical for control of WNV infection, are initiated by signaling through pathogen recognition receptors (PRR) such as RIG-I and MDA5. IPS-1 is a key adaptor in generating a PRR-dependent interferon response.. Here we show that IPS-1 deficiency in hematopoietic cells resulted in increased mortality and delayed WNV clearance from the brain. In IPS-1-/- mice, a dysregulated immune response was detected, characterized by a massive influx of macrophages and virus-specific T cells into the infected brain. These T cells were multifunctional and were able to lyse peptide-pulsed target cells in vitro. However, virus-specific T cells in the infected IPS-1-/- brain exhibited lower functional avidity than those in C57BL/6 brains, possibly contributing to less efficient virus clearance. The presence of virus-specific memory T cells was also not protective. We also show that macrophages were increased in numbers in the IPS-1-/- brain. Both macrophages and microglia exhibited an activated phenotype. Microarray analyses showed the preferential upregulation of genes associated with leukocyte activation and inflammation. Together, these results demonstrate the critical role that hematopoietic cell expression of Type 1 interferon and other IPS-1-dependent molecules have in WNV clearance and in regulating the inflammatory response. We used 4 mice in each group. STI knockout mice developed lethath encephalitis after WNV infectin. WT mice which have mild disease after WNV were used as controls.
2016-03-22 | E-GEOD-79417 | biostudies-arrayexpress
Project description:Expression data of Brain CD11b+ cells from WT and DP1I knockout mice
| PRJNA330771 | ENA
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:To investigate the in vivo metabolic changes during WNV infection in a mouse model, we infected mice with WNV NY99 to compare to uninfected (mock) mice. We also use two compounds targeting energetic metabolism to analysed their effects on WNV infection We then performed gene expression profiling analysis using data obtained from RNA-seq from infected vs uninfected mice and treated mice.
2023-09-27 | GSE233217 | GEO
Project description:To investigate the in vivo metabolic changes during WNV infection in a mouse model, we infected mice with WNV NY99 to compare to uninfected (mock) mice. We also use two compounds targeting energetic metabolism to analysed their effects on WNV infection We then performed gene expression profiling analysis using data obtained from RNA-seq from infected vs uninfected mice and treated mice.
2023-09-27 | GSE233216 | GEO
Project description:To investigate the in vivo metabolic changes during WNV infection in a mouse model, we infected mice with WNV NY99 to compare to uninfected (mock) mice. We also use two compounds targeting energetic metabolism to analyze their effects on WNV infection We then performed gene expression profiling analysis using data obtained from RNA-seq from infected vs uninfected mice and treated mice.
2023-09-27 | GSE233215 | 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.
2015-01-08 | GSE64735 | GEO
Project description:Flaviviruses, particularly Japanese encephalitis virus (JEV) and West Nile virus (WNV), are important causes of virus-induced central nervous system (CNS) disease in humans. We used microarray analysis to identify cellular genes that are differentially regulated following infection of the brain with JEV (P3) or WNV (New York 99). Gene expression data for these flaviviruses was compared to that induced following infection of the brain with reovirus (Type 3 Dearing), an unrelated neurotropic virus. Although several studies have described gene expression changes following virus infection of the brain, this report is the first to directly compare large-scale gene expression data from different viruses. We found that a large number of genes were up-regulated in common to infections with all 3 viruses (fold change > 2, P < 0.001), including genes associated with interferon signaling, the immune system, inflammation and cell death/survival signaling. In addition, genes associated with glutamate signaling were down-regulated in common to infections with all 3 viruses (fold change > 2, P < 0.001). These genes may serve broad spectrum therapeutic targets for virus-induced CNS disease. A distinct set of genes were up-regulated following flavivirus-infection, but not following infection with reovirus. These genes were associated with tRNA charging and may serve as therapeutic targets for flavivirus-induce CNS disease. Gene expression in the brain following WNV or JEV infection. WNV- or JEV-infected (N=3) vs. mock-infected (N=3) mouse brain.
2014-01-03 | E-GEOD-53784 | biostudies-arrayexpress
Project description:Greater than 50% of patients who survive neuroinvasive West Nile virus (WNV), a mosquito-borne, positive-sense strand flavivirus, exhibit cognitive sequelae including memory impairments which may last several years. High survival rates from WNV neuroinvasive disease (WNND) (>90%) have led to hundreds to thousands of cases of WNV-mediated neurologic impairment accruing annually, yet underlying mechanisms responsible for these impairments have not been investigated. Here, we established a novel murine model of recovery from WNND in which intracranial inoculation of a mutant WNV (WNV-NS5-E218A) leads to rates of survival and cognitive dysfunction that mirror human WNND. WNV-NS5-E218A-recovered mice exhibit impaired spatial learning and persistently phagocytic microglia without significant loss of hippocampal neurons or brain volume. Whole transcriptome analysis of hippocampi from WNV-NS5-E218A-recovered mice with poor spatial learning was performed in order to identify target pathways and molecules underlying cognitive impairments during WNND recovery. Total RNA obtained from isolated murine hippocampus at 25 days post-mock or WNV-NS5-E218A intracranial infection.
2016-06-27 | E-GEOD-72139 | biostudies-arrayexpress
Project description:West Nile virus (WNV) is an emerging mosquito-borne flavivirus, related to dengue virus and Zika virus. To gain insight into host pathways involved in WNV infection, we performed a systematic affinity-tag purification mass spectrometry (AP-MS) study to identify 259 WNV-interacting human proteins. RNAi screening revealed 26 genes that both interact with WNV proteins and influence WNV infection. We found that WNV, dengue and Zika virus capsids interact with a conserved subset of proteins that impact infection. These include the exon-junction complex (EJC) recycling factor, PYM1, which is antiviral against all three viruses. The EJC has roles in nonsense-mediated decay (NMD), and we found that both the EJC and NMD are antiviral. Mechanistically, we found that the EJC protein RBM8A directly binds WNV RNA. To counteract this antiviral defense, flavivirus infection inhibits NMD and the interaction of capsid with PYM1 interferes with EJC protein function and localization. Moreover, depletion of PYM1 attenuates RBM8A binding to viral RNA, suggesting that WNV sequesters PYM1 to protect viral RNA from decay. Together, these data suggest a complex interplay between the virus and host in regulating NMD and the EJC complex.
2019-11-14 | PXD011728 | Pride