Differential transcriptomic changes in the central nervous system and urinary bladders of mice infected with a coronavirus
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205772 | GEO | 2022/06/11
REPOSITORIES: GEO
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Project description:Background: Cystatin F is a secreted lysosomal cysteine protease inhibitor that has been implicated in affecting the severity of demyelination and enhancing remyelination in pre-clinical models of immune-mediated demyelination. How cystatin F impacts neurologic disease severity following viral infection of the central nervous system (CNS) has not been well characterized and was the focus of this study. We used cystatin F null-mutant mice (Cst7-/-) with a well-established model of murine coronavirus-induced neurologic disease to evaluate the contributions of cystatin F in host defense, demyelination and remyelination. Methods: Wildtype controls and Cst7-/- mice were intracranially (i.c.) infected with a sublethal dose of the neurotropic JHM strain of mouse hepatitis virus (JHMV), with disease progression and survival monitored daily. Immune cell infiltration into the brain and spinal cord was determined by flow cytometry. Spinal cord demyelination was determined by luxol fast blue (LFB) and Hematoxylin/Eosin (H&E) staining and remyelination evaluated by electron microscopy (EM) and calculation of g-ratios. Immune cell infiltration into the CNS and microglia activation were determined by flow cytometry and 10X genomics chromium 3’ single cell RNA sequencing (scRNAseq). Results: JHMV-infected Cst7-/- mice were able to control viral replication within the CNS, indicating that cystatin F is not essential for an effective Th1 anti-viral immune response. Infiltration of T cells and monocytes/macrophages into the spinal cords of JHMV-infected Cst7-/- mice was increased compared to infected controls, and this correlated with amplified demyelination and impaired remyelination. Single-cell RNA-seq of CD45+ cells enriched from spinal cords of infected Cst7-/- and control mice at day 21 post-infection (p.i.) revealed enhanced expression of transcripts encoding macrophage chemoattractant, Ccl2, and T cell chemoattractants, Cxcl9 and Cxcl10, combined with elevated expression of interferon-g (Ifng) transcripts and activation markers in CD8+ T cells from Cst7-/- mice compared to controls. Conclusions: Cystatin F is not required for immune-mediated control of JHMV replication within the CNS. However, JHMV-infected Cst7-/- mice exhibited more severe clinical disease associated with increased demyelination and impaired remyelination. The increase in disease severity was associated with elevated expression of macrophage and T cell chemoattractant chemokines, concurrent with increased neuroinflammation. These findings support the theory that one mechanism by which cystatin F affects chronic disease in mice persistently infected with JHMV is through regulating expression of pro-inflammatory molecules that impact neuroinflammation and neurologic disease.
2024-10-07 | GSE244656 | GEO
Project description:Differential transcriptomic changes in the central nervous system and urinary bladders of mice infected with a coronavirus
| PRJNA847561 | ENA
Project description:The present study examines functional contributions of microglia in host defense, demyelination, and remyelination following infection of susceptible mice with a neurotropic coronavirus. Treatment with PLX5622, an inhibitor of colony stimulating factor 1 receptor (CSF1R) that efficiently depletes microglia, prior to infection of the central nervous system (CNS) with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in increased mortality compared with control mice that correlated with impaired control of viral replication. Single cell RNA sequencing (scRNASeq) of CD45+ cells isolated from the CNS revealed that PLX5622 treatment resulted in muted CD4+ T cell activation profile that was associated with decreased expression of transcripts encoding MHC class II and CD86 in macrophages but not dendritic cells. Evaluation of spinal cord demyelination revealed a marked increase in white matter damage in PLX5622‐treated mice that corresponded with elevated expression of transcripts encoding disease‐associated proteins Osteopontin (Spp1), Apolipoprotein E (Apoe), and Triggering receptor expressed on myeloid cells 2 (Trem2) that were enriched within macrophages. In addition, PLX5622 treatment dampened expression of Cystatin F (Cst7), Insulin growth factor 1 (Igf1), and lipoprotein lipase (Lpl) within macrophage populations which have been implicated in promoting repair of damaged nerve tissue and this was associated with impaired remyelination. Collectively, these findings argue that microglia tailor the CNS microenvironment to enhance control of coronavirus replication as well as dampen the severity of demyelination and influence repair.
2022-10-21 | GSE215887 | GEO
Project description:Set of microarray experiments used to identify an unknown coronavirus in a viral culture derived from a patient with SARS. March 2003. Keywords = SARS Keywords = coronavirus Keywords = viral discovery Keywords = viruses Keywords = respiratory infection
2010-06-05 | E-GEOD-546 | biostudies-arrayexpress
Project description:Impaired type I interferon (IFN) responses are predictive of severe disease during pulmonary coronavirus infection. Insufficient IFN-responsiveness is associated with viremia and hypercytokinemia, however the resolution of IFN-dependent innate immune responses in the lungs remains limited. Here, we aimed to elucidate the early dynamics of antiviral immunity and define the IFN-dependent mechanisms limiting viral spread during pulmonary infection with the murine coronavirus A59 (M-CoV-A59), a beta-coronavirus. Combining high-resolution transcriptomic analysis and genetic attenuation of interferon signaling, we delineated IFN-dependent cell-intrinsic and population-based transcriptional changes that determined viral replication and inflammatory maturation, respectively.
2023-01-02 | E-MTAB-11781 | biostudies-arrayexpress
Project description:Differential expression was determined in Calu-3 cells between mock infected and infection with either Human coronavirus EMC and SARS coronavirus at different times post infection. Calu-3 2B4 cells were infected with Human Coronavirus EMC 2012 (HCoV-EMC) or mock infected. Samples were collected 0, 3, 7, 12, 18 and 24 hpi. There are 3 mock and 3 infected replicates for each time point, except for 12 hpi for which there are only 2 infected replicates (one replicate did not pass RNA quality check). There were no mock sampes at 18 hpi, and therefore infected samples at 18 hpi were compared with mocks at 24 hpi. For direct comparison with SARS-CoV infected cells, raw data from HCoV-EMC experiments were quantile normalized together with the SARS-CoV dataset (GEO Series accession number GSE33267).
2013-05-03 | E-GEOD-45042 | biostudies-arrayexpress
Project description:Set of microarray experiments used to identify an unknown coronavirus in a viral culture derived from a patient with SARS. March 2003. Keywords = SARS Keywords = coronavirus Keywords = viral discovery Keywords = viruses Keywords = respiratory infection Keywords: repeat sample
2003-10-19 | GSE546 | GEO
Project description:Differential expression was determined in Calu-3 cells between mock infected and infection with either Human coronavirus EMC and SARS coronavirus at different times post infection.
2013-05-03 | GSE45042 | GEO
Project description:The NanoString analysis of 770 genes expressed by 24 immune cell types in the tumors at 10 days after injection were performed. The Nanostring analysis uncovered marked difference in key immune regulatory networks associated with T, DC, NC and macrophage function
2019-03-04 | GSE127753 | GEO
Project description:Lasting behavioral and physiological changes such as abusive consumption, dependence, and withdrawal are characteristic features of alcohol use disorders (AUD). Mechanistically, persistent changes in gene expression are hypothesized to contribute to these brain adaptations leading to ethanol toxicity and abuse. Here we employed repeated chronic intermittent ethanol (CIE) exposure by vapor chamber as a mouse model to simulate the cycles of ethanol exposure and withdrawal commonly seen with AUD. This model has previously been shown to induce progressive ethanol consumption in rodents. Brain regional expression networks contributing to CIE-induced behavioral changes were identified by microarray analysis across five brain regions in the mesolimbic dopamine system and extended amygdala with tissue harvested from 0-120 hours following the last cycle of CIE. Weighted Gene Correlated Network Analysis (WGCNA) was used to identify gene networks over-represented for CIE-induced temporal expression changes across brain regions. Differential gene expression analysis of CIE vs. air-treated controls showed that long-lasting gene regulation occurred 5-days after the final cycle of ethanol exposure only in prefrontal cortex (PFC) and hippocampus. In the majority of brain-regions, however, ethanol regulated gene expression changes occurred only immediately following CIE or within the first 8-hours of removal from ethanol. Bioinformatics analysis of modules identified by WGCNA showed that neuroinflammatory responses were seen across multiple brain regions at early time-points, whereas co-expression modules related to neuroplasticity, chromatin remodeling, and neurodevelopment were seen at later time-points and in specific brain regions (PFC or HPC). In PFC a module containing Bdnf was identified as highly CIE responsive in a biphasic manner, with peak changes at 0 hours and 5 days following CIE, suggesting a possible role in mechanisms underlying long-term molecular and behavioral response to CIE. Strikingly, bioinformatics analysis of this network and several other modules identified Let-7 family microRNAs as potential regulators of gene expression changes induced by CIE. Our results suggest a complex temporal and regional pattern of widespread gene network responses involving neuroinflammatory and neuroplasticity related genes as contributing to physiological and behavioral responses to chronic ethanol. In particular, our identification of a potential role for Let-7 miRNAs and a Bdnf-related expression network in long-lasting expression changes after CIE may lead to future druggable gene target identification for novel intervention in AUD.
2016-04-15 | GSE72515 | GEO