ScRNAseq analysis of mouse draining lymph nodes during Ross River virus or LCMV infection
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE275970 | GEO | 2024/08/29
REPOSITORIES: GEO
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Project description:Chronic viral infections incapacitate adaptive immune responses by 'exhausting' virus-specific T cells, inducing their deletion and reducing productive T cell memory. Viral infection rapidly induces death receptor Fas (CD95) expression by dendritic cells (DCs) making them susceptible to elimination by the immune response. Lymphocytic Choriomeningitis Virus (LCMV) Clone 13, which normally establishes a chronic infection, is rapidly cleared in C57Black/J mice with conditional deletion of Fas in DCs. The immune response to LCMV is characterized by an extended survival of virus-specific effector T cells. Moreover, transfer of Fas-negative DCs from non-infected mice to already-infected animals results in either complete clearance of the virus or a significant reduction of viral titers. Thus, DC-specific Fas expression plays a role in regulation of anti-viral responses and suggests a strategy for stimulation of T cells in chronically infected animals and humans in order to achieve the clearance of persistent viruses. We compared gene expression between splenic DCs from B6.FasKI and B6.CD11c-Cre.FasKI mice. DCs were isolated on day 5 after LCMV infection with 3 mice in each group, for a total of 6 samples. Spleens were collagenase-DNAse digested and sorted by flow to isolate DCs.
2014-05-09 | E-GEOD-57443 | biostudies-arrayexpress
Project description:Chronic viral infections incapacitate adaptive immune responses by 'exhausting' virus-specific T cells, inducing their deletion and reducing productive T cell memory. Viral infection rapidly induces death receptor Fas (CD95) expression by dendritic cells (DCs) making them susceptible to elimination by the immune response. Lymphocytic Choriomeningitis Virus (LCMV) Clone 13, which normally establishes a chronic infection, is rapidly cleared in C57Black/J mice with conditional deletion of Fas in DCs. The immune response to LCMV is characterized by an extended survival of virus-specific effector T cells. Moreover, transfer of Fas-negative DCs from non-infected mice to already-infected animals results in either complete clearance of the virus or a significant reduction of viral titers. Thus, DC-specific Fas expression plays a role in regulation of anti-viral responses and suggests a strategy for stimulation of T cells in chronically infected animals and humans in order to achieve the clearance of persistent viruses.
2014-05-09 | GSE57443 | GEO
Project description:scRNAseq analysis of mouse draining lymph nodes during Ross River virus or LCMV infection
| PRJNA1153994 | ENA
Project description:Cytolytic activity by CD8+ cytotoxic T lymphocytes (CTL) is a powerful tactic in the elimination of intracellular pathogens and tumor cells. The destructive capacity of CTL is progressively dampened during chronic infection - yet the environmental cues and molecular pathways controlling immune “exhaustion” remain unclear. We find CTL immunity is regulated by the central transcriptional response to hypoxia, mediated by the von-Hippel-Lindau/Hypoxia-Inducible-Factor (VHL/HIF) pathway. Deletion of VHL, the primary negative regulator of HIF, leads to lethal CTL-mediated immunopathology during chronic infection, and VHL-deficient CTL display enhanced control of persistent viral infection and neoplastic growth. We find HIF and oxygen influence expression of pivotal CTL transcription, effector and costimulatory-inhibitory molecules, which is relevant to strategies to promote viral and tumor clearance. To understand the role of the VHL/HIF pathway in regulating T cell responses to acute and persistant antigen in vivo, a mixture of ~10^4 WT and Vhl KO virus-specific CD8+ T cells (P14s) was transferred iv into uninfected WT host mice. After infection with either LCMV-Armstrong (acute viral infection) or LCMV-clone13 (persistent viral infection) we double-FACS isolated the responding P14 donor cells from pooled spleens from two sets of host mice to obtain duplicates for microarray for the four conditions, resulting in eight samples (2 WT Arm, 2 VHL KO Arm; 2 WT cl13, 2 VHL KO cl13) at 6 to 7 days post-infection. All conditions were sorted on KRLG1lo P14 cells. Note this was a mixed P14 transfer, so WT and KO cells were responding to infection in the same WT host mice to aid in normalizing effects such as antigen load and cytokine environment.
2013-09-29 | E-GEOD-50158 | biostudies-arrayexpress
Project description:CD4+ T cells play a critical role in sustaining the effector function of CD8+ T cells during chronic viral infection. When CD4+ T cell “help” is absent, CD8+ T cells enter a dysfunctional state, losing their capacity for viral control. However, when CD4+ T cell help is present, a heterogenous population of virus-specific CD8+ T cells are present. Here, we applied scRNA-seq to distinguish CD8+ T cell heterogeneity during LCMV Clone 13 infection.
2022-11-29 | GSE201195 | GEO
Project description:Viruses often establish persistent infections by interrupting immune cell responses. Sphingosine kinase 2 (SphK2) generates sphingosine 1-phsophate, which is known to regulate versatile cellular processes, including immune responses. However, little is known about the role of SphK2 in the immune response to viral infections. Here, we demonstrate that during lymphocytic choriomeningitis virus (LCMV) clone 13 infection, a virus known to establish a persistent infection in mice, SphK2 functions to limit CD4+ T cell responses, which aids in the establishment of virus-induced immunosuppression and viral persistence. The infection of SphK2-deficient (Sphk2-/-) mice with LCMV resulted in kidney disease and ultimately mortality. Following infection, Sphk2-/- mice were shown to have increased LCMV-specific CD4+ and CD8+ T cell responses. With the use of LCMV epitope-specific TCR transgenic mouse lines in adoptive transfer studies, SphK2 was shown to have intrinsic negative function in CD4+ T cells, but not CD8+ T cells. Furthermore, Sphk2-/- CD4+ T cells were able to promote endogenous, virus-specific CD8+ T cell responses more efficiently than Sphk2+/+ CD4+ T cells. Our results suggest that SphK2 is a novel regulator of the immune response during LCMV clone 13 infection and targeting SphK2 may provide a promising immunotherapeutic strategy for the control of persistent viral infections. This study incorporated the use of RNA sequencing to determine what pathways SphK2 was involved in to affect CD4+ T cell activity and proliferation. Sphk2+/+ or Sphk2-/- LCMV epitope-recognizing tg CD4+ T cells were transferred into C57BL/6 mice and recovered 7 days following LCMV Cl 13 infection. RNA sequencing revealed several pathways upregulated in Sphk2-/- CD4+ T cells relating to cell cycle progression, regulation of transcription, and regulation of nucleic acid binding.
2020-10-29 | GSE155030 | GEO
Project description:Single-cell immune repertoire sequencing (gene expression and immune receptor repertoire) was performed under various contexts. This includes CD4 T follicular cells (sorted by surface expression of PD1+ CXCR5+ CD4+) following high dose LCMV clone 13 infection on days 10, 25, and 50 and low dose clone 13 infection on day 10 post infection. We additionally profiled virus-specific CD8 T cells that are specific to either GP33 or NP396. Gp33-specific CD8 T cells were sorted 15 months post infection with either low dose clone 13 LCMV, MCMV-ie2-gp33 or MCMV-m45-gp33. NP396-specific CD8 T cells were isolated either 10 days post challenge or 25 days post challenge using the viral model of dejavu (https://pubmed.ncbi.nlm.nih.gov/16604192/). B and T cells were isolated 14 days post induction of Experimental autoimmune encephalomyelitis (EAE).
2022-02-01 | E-MTAB-11330 | biostudies-arrayexpress
Project description:Several viruses can infect the mammalian nervous system and induce neurological dysfunction. Adoptive immunotherapy (AI) is an approach that involves administration of antiviral T cells and has shown promise in clinical studies for the treatment of peripheral virus infections in humans such as cytomegalovirus, Epstein-Barr virus, and adenovirus, among others. Clearance of neurotropic infections, on the other hand, is particularly challenging because the central nervous system (CNS) is relatively intolerant of immunopathological reactions. Therefore, it is essential to develop and mechanistically understand therapies that noncytopathically eradicate pathogens from the CNS. Here, we used mice persistently infected from birth with lymphocytic choriomeningitis virus (LCMV) to demonstrate that therapeutic antiviral T cells can completely purge the persistently infected brain without causing blood brain barrier breakdown or tissue damage. Mechanistically, this is accomplished through a tailored release of chemoattractants that recruit antiviral T cells, but few pathogenic innate immune cells such as neutrophils and inflammatory monocytes. Upon arrival, T cells enlisted the support of nearly all brain resident myeloid cells (microglia) by converting them into CD11c+ antigen-presenting cells (APCs) – a cell population also found in the brain of a human immunodeficiency virus infected patient. Two-photon imaging studies revealed that antiviral CD8+ and CD4+ T cells interacted directly with CD11c+ microglia and induced STAT1 signaling, but did not initiate programmed cell death. We propose that noncytopathic CNS viral clearance can be achieved by therapeutic antiviral T cells reliant on restricted chemoattractant production and interactions with apoptosis-resistant microglia. 6 Mouse Microglia-sorted Brain Samples: 3 (-) AI, 3 (+) AI.
2015-06-22 | E-GEOD-66421 | biostudies-arrayexpress
Project description:The goal of this study was to identify the molecular programming using ATAC-seq of CD8 T cells responding to different viral infections. Mice were infected with either LCMV Armstrong to model an acute infection or LCMV Clone-13 to model a chronic infection. At various time points following infection, virus-specific CD8 T cells were purified and ATAC-seq performed. These data identify the changes in chromatin accessibility associated with acute infections and the establishment of functional memory versus those accessibility changes associated with chronic infection.
2017-01-31 | GSE83081 | GEO
Project description:Necroptosis is a lytic and inflammatory form of cell death that is highly constrained to mitigate detrimental collateral tissue damage and impaired immunity. These constraints make it difficult to define the relevance of necroptosis in diseases such as chronic and persistent viral infections and within individual organ systems. The role of necroptotic signalling is further complicated because proteins essential to this pathway, such as receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), have been implicated in roles outside of necroptotic signalling. We sought to address this issue by individually defining the role of RIPK3 and MLKL in chronic lymphocytic choriomeningitis virus (LCMV) infection. We investigated if necroptosis contributes to the death of LCMV-specific CD8+ T cells or virally infected target cells during infection. We provide evidence showing that necroptosis was redundant in the pathogenesis of acute forms of LCMV (Armstrong strain) and the early stages of chronic (Docile strain) LCMV infection in vivo. The number of immune cells, their specificity and reactivity towards viral antigens and viral loads are not altered in the absence of either MLKL or RIPK3 during acute and during the early stages of chronic LCMV infection. However, we identified that RIPK3 promotes immune dysfunction and prevents control of infection at later stages of chronic LCMV disease. This was not phenocopied by the loss of MLKL indicating that the phenotype was driven by a necroptosis-independent function of RIPK3. We provide evidence that RIPK3 signaling evoked a dysregulated type 1 interferone response which we linked to an impaired antiviral immune response and abrogated clearance of chronic LCMV infection.
2023-03-12 | GSE224066 | GEO