Temporally resolved single-cell RNA sequencing reveals protective and pathological responses during herpes simplex virus 1 CNS infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE283518 | GEO | 2025/06/01
REPOSITORIES: GEO
Similar Datasets
Project description:The overall goal of the study was to use in vivo data combined with functional genomics to define gene expression signatures representative of a spectrum of HSV CNS infections. Innate immune deficiencies result in a spectrum of severe clinical outcomes following infection. In particular, there is a strong association between loss of the signal transducer and activator of transcription (Stat) pathway, breach of the blood-brain barrier (BBB), and virus-induced neuropathology. The gene signatures that characterize resistance, disease, and mortality in the virus-infected nervous system have not been defined. Herpes simplex virus type 1 (HSV-1) is commonly associated with encephalitis in humans, and humans and mice lacking Stat1 display increased susceptibility to HSV central nervous system (CNS) infections. In this study, two HSV-1 strains were used, KOS (wild type [WT]), and Δvhs, an avirulent recombinant lacking the virion host shutoff (vhs) function. In addition, two mouse strains were used: strain 129 (control) and a Stat1-deficient (Stat1(-/-)) strain. Using combinations of these virus and mouse strains, we established a model of infection resulting in three different outcomes: viral clearance without neurological disease (Δvhs infection of control mice), neurological disease followed by viral clearance (Δvhs infection of Stat1(-/-) mice and WT infection of control mice), or neurological disease followed by death (WT infection of Stat1(-/-) mice). Through the use of functional genomics on the infected brain stem and liver, we determined gene signatures that were representative of the three infection outcomes. Gender matched, 6- to 8- week old immunocompetent, control 129S6 and 129S6 Stat1 knockout mice were infected corneally with 2x10^6 PFU of either wild type HSV-1, a vhs-null HSV virus, or mock-infected. Brain stems and liver of individual mice were isolated at days 1, 3, 5 and 7 post-inoculation for microarray analysis. For microarray analysis, samples were collected from n=2 animals (1 male, 1 female) per mouse strain and virus strain for each time point. Equal masses of tissue were pooled from two mock-infected mice per time point and run on microarray.
2012-02-21 | E-GEOD-35943 | biostudies-arrayexpress
Project description:Herpes simplex virus mutants lacking the vhs gene are severely attenuated in animal models of pathogenesis and exhibit reduced growth in primary cell culture. As a result of these properties vhs-deleted virus have been proposed as live-attenuated viruses. Despite these findings and their implications for vacccines, the mechanisms by which vhs promotes infection in cell culture and in vivo are not understood. In this study we demonstrate that vhs-deficent viruses replicate to reduced levels in interferon(IFN)- primed cells. Furthermore, vhs-defective viruses induce increased levels of IFN? and IFN?-stimulated genes, and increased levels of eIF2? phosphorylation in infected cells. In addition, we demonstrate a generalized over-expression of viral RNAs following infection with a vhs-deficient virus. This suggests increased expression of IFN pathway inducing double stranded RNA, a potent pathogen-associated molecular pattern (PAMP). Together these data show that vhs likely functions to reduce innate immune responses and thereby acts as critical determinant of viral pathogenesis. Keywords: time course, genetic modification Time course (1,3,6,9 & 12h) of HSV infected mouse embryo fibroblasts. Wild type (KOS) virus is co-hybridized with vhs null virus (NHB). Each time-point is hybridized in quadruplicate.
2008-04-03 | E-GEOD-10962 | biostudies-arrayexpress
Project description:The overall goal of the study was to use in vivo data combined with functional genomics to define gene expression signatures representative of a spectrum of HSV CNS infections. Innate immune deficiencies result in a spectrum of severe clinical outcomes following infection. In particular, there is a strong association between loss of the signal transducer and activator of transcription (Stat) pathway, breach of the blood-brain barrier (BBB), and virus-induced neuropathology. The gene signatures that characterize resistance, disease, and mortality in the virus-infected nervous system have not been defined. Herpes simplex virus type 1 (HSV-1) is commonly associated with encephalitis in humans, and humans and mice lacking Stat1 display increased susceptibility to HSV central nervous system (CNS) infections. In this study, two HSV-1 strains were used, KOS (wild type [WT]), and Δvhs, an avirulent recombinant lacking the virion host shutoff (vhs) function. In addition, two mouse strains were used: strain 129 (control) and a Stat1-deficient (Stat1(-/-)) strain. Using combinations of these virus and mouse strains, we established a model of infection resulting in three different outcomes: viral clearance without neurological disease (Δvhs infection of control mice), neurological disease followed by viral clearance (Δvhs infection of Stat1(-/-) mice and WT infection of control mice), or neurological disease followed by death (WT infection of Stat1(-/-) mice). Through the use of functional genomics on the infected brain stem and liver, we determined gene signatures that were representative of the three infection outcomes.
2012-02-21 | GSE35943 | GEO
Project description:We describe the cellular response to HSV-1 infection in human iPSC-derived brain organoids
2021-01-22 | GSE163952 | GEO
Project description:Chronic viral infections are difficult to treat and new approaches, particularly those involving enhancing immune responses are needed. Herpes simplex virus (HSV) establishes latency, reactivates frequently, and breakthrough reactivation can occur despite suppressive antiviral therapy. Virus-specific T cells are important to control HSV, and activated T cells require increased metabolism of glutamine for their proliferation. We found that treatment of HSV-1 latently infected mice and HSV-2 infected guinea pigs with supplemental oral glutamine reduced virus reactivation. Transcriptome analysis of mice treated with glutamine showed that several interferon (IFN)-γ inducible genes were upregulated. Unlike wild-type mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in IFN-γ knock-out mice. Mice treated with glutamine had higher numbers of HSV-specific IFN-γ producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-γ-associated immune response and reduce the rate of reactivation of latent virus infection.
2017-08-30 | GSE95715 | GEO
Project description:Chronic viral infections are difficult to treat and new approaches, particularly those involving enhancing immune responses are needed. Herpes simplex virus (HSV) establishes latency, reactivates frequently, and breakthrough reactivation can occur despite suppressive antiviral therapy. Virus-specific T cells are important to control HSV, and activated T cells require increased metabolism of glutamine for their proliferation. We found that treatment of HSV-1 latently infected mice and HSV-2 infected guinea pigs with supplemental oral glutamine reduced virus reactivation. Transcriptome analysis of mice treated with glutamine showed that several interferon (IFN)-γ inducible genes were upregulated. Unlike wild-type mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in IFN-γ knock-out mice. Mice treated with glutamine had higher numbers of HSV-specific IFN-γ producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-γ-associated immune response and reduce the rate of reactivation of latent virus infection.
2017-08-30 | GSE95714 | GEO
Project description:Chronic viral infections are difficult to treat and new approaches, particularly those involving enhancing immune responses are needed. Herpes simplex virus (HSV) establishes latency, reactivates frequently, and breakthrough reactivation can occur despite suppressive antiviral therapy. Virus-specific T cells are important to control HSV, and activated T cells require increased metabolism of glutamine for their proliferation. We found that treatment of HSV-1 latently infected mice and HSV-2 infected guinea pigs with supplemental oral glutamine reduced virus reactivation. Transcriptome analysis of mice treated with glutamine showed that several interferon (IFN)-γ inducible genes were upregulated. Unlike wild-type mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in IFN-γ knock-out mice. Mice treated with glutamine had higher numbers of HSV-specific IFN-γ producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-γ-associated immune response and reduce the rate of reactivation of latent virus infection.
2017-08-30 | GSE95713 | GEO
Project description:Herpes simplex virus mutants lacking the vhs gene are severely attenuated in animal models of pathogenesis and exhibit reduced growth in primary cell culture. As a result of these properties vhs-deleted virus have been proposed as live-attenuated viruses. Despite these findings and their implications for vacccines, the mechanisms by which vhs promotes infection in cell culture and in vivo are not understood. In this study we demonstrate that vhs-deficent viruses replicate to reduced levels in interferon(IFN)- primed cells. Furthermore, vhs-defective viruses induce increased levels of IFNβ and IFNβ-stimulated genes, and increased levels of eIF2α phosphorylation in infected cells. In addition, we demonstrate a generalized over-expression of viral RNAs following infection with a vhs-deficient virus. This suggests increased expression of IFN pathway inducing double stranded RNA, a potent pathogen-associated molecular pattern (PAMP). Together these data show that vhs likely functions to reduce innate immune responses and thereby acts as critical determinant of viral pathogenesis. Keywords: time course, genetic modification
2008-04-03 | GSE10962 | GEO
Project description:The brain is highly sensitive to damage caused by infection and inflammation. Herpes simplex virus-1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Using genome-wide CRISPR screening for HSV-1 restriction factors, we identified TMEFF1, which is expressed specifically in CNS neurons and not regulated by type I interferon, as the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death upon HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with Nectin-1 and non-muscle myosin heavy chain IIA/B, which are core proteins in virus-cell binding and virus-cell fusion, respectively. Importantly, Tmeff1-/- mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the CNS.
2024-07-24 | GSE268182 | GEO
Project description:The goal of this study was to compare small RNA profiles (sRNA-seq) of HSV-1 infected and mock infected human fibroblast KMB17 strain at 48 hours post infection.
2017-08-10 | GSE102470 | GEO