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.
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.
Project description:The host innate immune response to influenza virus is a key determinant of pathogenic outcomes and long-term protective responses against subsequent exposures. Comparison of the transcriptional profiles obtained 24 and 36 hrs post-infection showed that the magnitude of gene expression was greater in LAIV infected cells relative to that observed in WT infected cells. Functional enrichment analysis revealed that the antiviral and inflammatory responses was largely driven by type III IFN induction in both WT and LAIV infected cells. However, the enrichment of biological pathways involved in the recruitment of mononuclear leukocytes, antigen presenting cells, and T lymphocytes was uniquely observed in LAIV infected cells. These findings indicate that cell-intrinsic type III IFN-mediated innate immune responses in the nasal epithelium are not only crucial for viral clearance and attenuation, but may also play an important role in the immunogenicity of live-attenuated vaccines
Project description:The host innate immune response to influenza virus is a key determinant of pathogenic outcomes and long-term protective responses against subsequent exposures. Comparison of the transcriptional profiles obtained 24 and 36 hrs post-infection showed that the magnitude of gene expression was greater in LAIV infected cells relative to that observed in WT infected cells. Functional enrichment analysis revealed that the antiviral and inflammatory responses was largely driven by type III IFN induction in both WT and LAIV infected cells. However, the enrichment of biological pathways involved in the recruitment of mononuclear leukocytes, antigen presenting cells, and T lymphocytes was uniquely observed in LAIV infected cells. These findings indicate that cell-intrinsic type III IFN-mediated innate immune responses in the nasal epithelium are not only crucial for viral clearance and attenuation, but may also play an important role in the immunogenicity of live-attenuated vaccines
Project description:Borna disease virus (BoDV-1) is a highly neurotropic RNA virus, which causes neurobehavioral disturbances such as abnormal social activities and memory impairment. In this study, we investigated the effects of BoDV-1 infection on neuronal differentiation and transcriptome of differentiated neuronal cells using persistently BoDV-1-infected SH-SY5Y (SB) cells. Differentiated neuronal cells exhibited transcriptomic changes of genes related to neurite outgrowth and antiviral immune system.
Project description:Antiviral CD8+ T cell immunity depends on the integration of various contextual cues, but how antigen-presenting cells (APCs) consolidate these signals for decoding by T cells remains unclear. Here, we describe gradual interferon-α/interferon-β (IFNα/β)-induced transcriptional adaptations that endow APCs with the capacity to rapidly activate the transcriptional regulators p65, IRF1 and FOS after CD4+ T cell-mediated CD40 stimulation. While these responses operate through broadly used signaling components, they induce a unique set of co-stimulatory molecules and soluble mediators that cannot be elicited by IFNα/β or CD40 alone. This response is critical for the acquisition of antiviral CD8+ T cell effector function, and its activity in APCs from individuals infected with severe acute respiratory syndrome coronavirus 2 correlates with milder disease. These observations uncover a sequential integration process whereby APCs rely on CD4+ T cells to select the innate circuits that guide antiviral CD8+ T cell responses.
Project description:Antiviral CD8+ T cell immunity depends on the integration of varying contextual cues, but how antigen presenting cells (APC ) consolidate these signals for decoding by T cells remains unclear. We describe gradual IFN-α/β-induced transcriptional adaptations that endowed APC with the capacity to rapidly activate the transcriptional regulators P65, IRF1 and FOS upon CD4+ T cell-mediated CD40 stimulation. While these responses operated through broadly utilized signaling components, they induced a unique set of costimulatory molecules and soluble mediators that could not be elicited by IFN-α/β or CD40 alone. This response was critical for the acquisition of antiviral CD8+ T cell effector function, and its activity in APC from patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) correlated with milder disease. These observations uncover a sequential integration process whereby APC rely on CD4+ T cells to select the innate circuits that guide antiviral CD8+ T cell responses.
Project description:Resident and infiltrating myeloid cells are frequently reported to be tumor-promoting upon incidence of BCBM, but these cells are often poorly discriminated. We utilized scRNAseq to transcriptionally discriminate key immune cell populations and identify that microglia are predominantly pro-inflammatory upon BCBM initiation, and driven to an antigen presenting phenotype by infiltrating T cells.