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A divergent and complementary transcriptional response in poxvirus-infected and bystander inflammatory monocytes is partly dictated by interferon [iMO IFN ECTV]

ABSTRACT: Inflammatory monocytes (iMO) and B-cells are the main targets of the poxvirus ectromelia virus (ECTV) in the lymph nodes of mice and play distinct roles in surviving the infection. Infected and bystander iMO control ECTV’s systemic spread, preventing early death, while B-cells make antibodies that eliminate ECTV. Our work demonstrates that within an infected animal that survives ECTV infection, intrinsic and bystander infection of iMO and B-cells differentially control the transcription of genes important for immune cell function and, perhaps, cell identity. Bystander cells upregulate metabolism, antigen presentation, and interferon-stimulated genes. Infected cells downregulate many cell-type-specific genes and upregulate transcripts typical of non-immune cells. Bys and Inf iMO non-redundantly contribute to the cytokine milieu and the interferon response. Furthermore, we uncovered how IFN-I or IFN-γ signaling differentially regulates immune pathways in Inf and Bys iMO and, that at steady state, IFN-I primes iMO for rapid IFN-I production and antigen presentation.

ORGANISM(S): Mus musculus

PROVIDER: GSE215745 | GEO | 2022/10/18

REPOSITORIES: GEO

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A divergent and complementary transcriptional response in poxvirus-infected and bystander inflammatory monocytes is partly dictated by interferon [iMO_Bcells_ECTV]

Project description:Inflammatory monocytes (iMO) and B-cells are the main targets of the poxvirus ectromelia virus (ECTV) in the lymph nodes of mice and play distinct roles in surviving the infection. Infected and bystander iMO control ECTV’s systemic spread, preventing early death, while B-cells make antibodies that eliminate ECTV. Our work demonstrates that within an infected animal that survives ECTV infection, intrinsic and bystander infection of iMO and B-cells differentially control the transcription of genes important for immune cell function and, perhaps, cell identity. Bystander cells upregulate metabolism, antigen presentation, and interferon-stimulated genes. Infected cells downregulate many cell-type-specific genes and upregulate transcripts typical of non-immune cells. Bys and Inf iMO non-redundantly contribute to the cytokine milieu and the interferon response. Furthermore, we uncovered how IFN-I or IFN-γ signaling differentially regulates immune pathways in Inf and Bys iMO and, that at steady state, IFN-I primes iMO for rapid IFN-I production and antigen presentation.

2022-10-18 | GSE215746 | GEO

SARS-CoV-2 infection of human pluripotent stem cell-derived liver organoids reveals potential mechanisms of liver pathology (scRNA-Seq)

Project description:Symptoms of liver damage are observed in nearly half of patients that succumb to severe SARS-CoV-2 infection. Here we use human induced pluripotent stem cell-derived liver organoids (HLOs) to recapitulate and characterize liver pathology following virus exposure. Utilizing single-cell sequencing technology, we identified robust transcriptomic changes that occur in SARS-CoV-2 infected liver cells as well as uninfected bystander cells. Our results show a significant induction of many inflammatory pathways, including IFN-α, INF-γ and IL-6 signaling. Our results further identify IL-6 signaling as a potential mechanism for liver-mediated activation of circulating macrophages.

2022-10-04 | GSE210059 | GEO

SARS-CoV-2 infection of human pluripotent stem cell-derived liver organoids reveals potential mechanisms of liver pathology (Bulk RNA-Seq)

2022-10-04 | GSE210058 | GEO

Comparison of host gene expression profiles in spleen tissues of genetically susceptible and resistant mice during ECTV infection

Project description:Ectromelia virus (ECTV) has emerged as a valuable model for investigating the host-orthopoxvirus relationship as it relates to pathogenesis and the immune response. ECTV causes mousepox in most strains of mice, including BALB/c and DBA/2, and these are therefore classified as susceptible mice. Conversely, C57BL/6 and certain 129 strains display limited pathology and a very low mortality, and are thus classified as resistant. To understand the host genetic factors of different mouse strains in response to ECTV infection, we carried out a microarray analysis using Affymetrix Gene-Chip Mouse Genome Arrays of spleen tissues from BALB/c and C57BL/6 mice at 3 and 10 days post-ECTV infection. Differential Expression of Genes (DEGs) analyses revealed distinct differences in the gene profiles of resistant and susceptible mice infected with ECTV. Gene ontology and KEGG pathway analysis showed that the DEGs of susceptible mice were involved mainly in immunity, apoptosis, spliceosomes and cancer-related pathways, while the DEGs of resistant mice were largely involved in MAPK signaling and leukocyte transendothelial migration. This suggests that the susceptible BALB/c mice have a stronger response than the resistant C57BL/6 mice to ECTV infection. The BALB/c mice showed a strong induction of interferon-induced genes (ISGs), including guanylate binding proteins (GBPs), myxovirus resistance protein (Mx) GTPases, oligoadenylate synthetase (OAS) and IFN-induced protein with tetratricopeptide repeats (IFIT) family proteins, while the C57BL/6 mice upregulated more genes related to metabolic pathways. This suggests that the susceptible BALB/c mice have a stronger response than the resistant C57BL/6 mice to ECTV infection.

2018-02-16 | GSE100644 | GEO

Cross-presenting CD103+ dendritic cells are protected from influenza virus infection

Project description:CD8+ cytotoxic T cells are critical for viral clearance from the lungs upon influenza virus infection. The contribution of cross-presentation to the induction of anti-viral cytotoxic T cells remains debated. Here, we used a recombinant influenza virus expressing a NS1-GFP reporter gene to visualize the route of antigen presentation by lung dendritic cells (DC) upon viral infection in vivo. We found that lung CD103+ DC are the only subset to carry intact GFP protein to the draining lymph nodes. Strikingly, lung migratory CD103+ DC are not productively infected by influenza virus and thus induce virus-specific CD8+ T cells through the cross-presentation of antigens from virally infected cells. We also show that CD103+ DC resistance to infection correlates with an increased antiviral state in these cells that is dependent on the expression of IFN receptor alpha. In conclusion, these results establish that efficient cross-priming by migratory lung DC is coupled to the acquisition of an anti-viral status, which is dependent on type I IFN signaling pathway. mRNA profiles were generated by deep-sequencing in Illumina HiSeq2000 from alveolar macrophages and CD103+ dendritic cells from lungs of untreated and flu-treated mice

2013-06-19 | E-GEOD-38838 | biostudies-arrayexpress

Role of interferon-alpha in the activation of tubular epithelial cell in lupus nephritis (LN)

Project description:Plasmacytoid dendritic cells (pDCs) play a key role in the activation of the autoimmune response in LN. Recently we demonstrated that these cells infiltrate the kidney of patients with LN at tubulointerstitial level. The pDCs are the main producers of IFN-alpha, whose effects on the renal tubule are poorly understood. The aim of the study was to investigate the effects of INF-alpha in renal epithelial cells (RPTEC). We investigated the effect of IFN-alpha on the whole-genome gene expression profile in RPTEC cells,. Genomic analysis showed that after stimulation, 108 genes are up-regulated and only 7 are down-regulated, with a fold-change> 2. The Gene Set Enrichment analysis confirmed that IFN-alpha induced the pathway of antigen presentation and the inflammatory signaling in RPTEC. Among the up-regulated genes involved in these pathways, there were HLA-I, the ubiquitins (FBXO6 and DTX3L) and the immunoproteasome subunits LMP7. We performed the validation of these genes by real time PCR and citometry experiments on RPTEC stimulated with IFN-alpha. Immunohistochemical analysis of LMP7 and MXA protein, specific marker of IFN-alpha, showed a significant upregulatation of both proteins in renal biopsies of patients with LN class IV compared to class I. Confocal microscopy showed the colocalization of LMP7-MXA in tubular epithelium of patients with LN class IV and activation of inflammatory signaling via NF-kB in the MXA+ tubules. Our data suggested that inhibition of INF-alpha pathways could represent a novel therapeutic strategy to reduce renal tubular damage in patients with LN. To identify genes specifically modulated by INF-alpha in RPTEC, we stimulated 3 different cell clones with 100U/ml INF-alpha for 48 hours and compared their whole-genome gene expression profiles with that from 3 RPTEC clones cultured without stimuli.

2015-12-15 | E-GEOD-48551 | biostudies-arrayexpress

Cross-presenting CD103+ dendritic cells are protected from influenza virus infection

2013-06-19 | GSE38838 | GEO

Transcription profiling of human CD4+ memory T cells reveals they are preferential targets for bystander activation and apoptosis

Project description:There is much evidence that T cells may be activated via mechanisms which act independently of direct TCR ligation. Despite this, the question of whether such forms of âbystanderâ T cell activation occur during immune responses is hotly debated. To address some outstanding questions, we set up an in vitro system within which to analyse bystander T cell activation in human T cells, in the absence of the possibility for TCR cross-reactivity. In addition, we have investigated the genetic, phenotypic, and functional characteristics of bystander activated T cells. Here, we show that bystander T cell activation is, indeed, observed during a specific immune response, and that it occurs preferentially amongst CD4+ memory T cells. Furthermore, bystander activated T cells display a distinct gene expression profile. The mechanism for bystander T cell activation involves soluble factors, and the outcome is an elevated level of apoptosis. This may provide an explanation for the attrition of T cell memory pools of heterologous specificity during immune responses to pathogens such as viruses. Experiment Overall Design: Three conditions tested with 4 biological repilicates in each: Experiment Overall Design: Resting cells - cells expressing a TCR which does not specifically recognize SEB (VÎ²13.1 T cells) and did not upregulate the activation marker CD25 in response to transwell SEB-stimulated co-culture over a 5 day period. Experiment Overall Design: Bystander activated cells - cells expressing a TCR which does not specifically recognize SEB (VÎ²13.1 T cells), but which did upregulate the activation marker CD25 in response to transwell SEB-stimulated co-culture over a 5 day period. Experiment Overall Design: Directly activated cells - cells expressing a TCR which is known to specifically recognize SEB (VÎ²17 T cells), and which did upregulate the activation marker CD25 in response to direct SEB stimulation over a 5 day period.

2009-02-21 | E-GEOD-13738 | biostudies-arrayexpress

Transcriptional profiling reveals differential effect of in vivo porcine reproductive and respiratory syndrome virus infection on infected and bystander pulmonary alveolar macrophage cells

Project description:Porcine reproductive and respiratory syndrome virus (PRRSV) remains a serious threat to the swine industry worldwide for many years. PRRSV has a high tropism for swine pulmonary alveolar macrophages (PAM), an essential innate immune cell. Here, we used RNA-sequencing approach to examine the transcriptional profile of in vivo infected and bystander PAM in the lung of PRRSV-infected swine at 7 days post-infection (dpi). We utilize the PRRSV virion stably expressing EGFP reporter gene to discriminate infected and bystander PAM cells. This work will allow us to differentiate the direct and indirect effect of infection at the cellular level. Firstly, average ~4.2% of reads from infected, while only ~0.06 % reads from bystander cells found mapping to the FL12-EGFP genome. Though most differentially expressed genes (DEGs) are shared between infected and bystander PAM compared to PAM from mock-infected animals, infected cells produce more inflammatory cytokines, interferon signatures, and antiviral immune genes than bystander cells. Importantly, upregulation of NFKB inhibitors (NFKBI) (NFKBIA, NFKBIZ, and TNFAIP3) and T cell exhaustion genes (PD-L1 (CD274), PRDM1, and IL10) was exclusively observed in infected cells. In-situ staining of lung tissue using NFKBI RNA probes confirms temporal upregulation of these immune regulators. Both NFKBI and T-cell exhaustion are prominent immune escape mechanism noted in a several viral infections, however, their role is unexplored in PRRSV pathogenesis. Collectively, these results reveal distinctive transcriptional changes occur within infected and bystander PAM and unique upregulation of NFKBI and T-cell exhaustion pathway in infected PAM indicates a strategy employ by PRRSV to subverts host immune responses.

2021-08-06 | GSE174494 | GEO

Expression data from WT and Klrc1-/- CD8+ T cells

Project description:CD8+ T cells and NK cells protect from viral infections by killing virally-infected cells and secreting interferon-g. Several inhibitory receptors limit the magnitude and duration of these anti-viral responses. We used microarrays to assess the transcriptome of ectromelia virus (ECTV) specific CD8+ T cells that genetically lack one such receptor, NKG2A, which is encoded by Klrc1. NaÃ¯ve or ECTV-specific CD8+ T cells were sorted directly into RLT buffer. RNA was then extracted, processed, and hybridized to Affymetrix arrays.

2015-11-07 | E-GEOD-74780 | biostudies-arrayexpress

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