Theiler’s Virus-Mediated Immunopathology in the CNS and Heart: Roles of Organ-Specific Cytokine and Lymphatic Responses
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ABSTRACT:
PROVIDER: PRJNA491435 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR7852040_1.fastq.gz | Fastqsanger.gz | |||
| SRR7852040_2.fastq.gz | Fastqsanger.gz | |||
| SRR7852050_1.fastq.gz | Fastqsanger.gz | |||
| SRR7852050_2.fastq.gz | Fastqsanger.gz | |||
| SRR7852060_1.fastq.gz | Fastqsanger.gz |
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Project description:Theiler’s murine encephalomyelitis virus (TMEV) induces different diseases in the central nervous system (CNS) and heart, depending on the mouse strains and time course, where cytokines play a key role for viral clearance and immune-mediated pathology (immunopathology). In SJL/J mice, TMEV infection causes chronic TMEV-induced demyelinating disease (TMEV-IDD) in the spinal cord around 1 month post infection (p.i.). Unlike other immunopathology models, both pro-inflammatory and anti-inflammatory cytokines can play dual roles in TMEV-IDD. Pro-inflammatory cytokines play a beneficial role in viral clearance while they also play a detrimental role in immune-mediated demyelination. Anti-inflammatory cytokines suppress not only protective anti-viral immune responses but also detrimental autoreactive immune responses. On the other hand, in C3H mice, TMEV infection induces a non-CNS disease, myocarditis, with three phases: phase I, viral pathology with interferon and chemokine responses; phase II, immunopathology mediated by acquired immune responses; and phase III, cardiac fibrosis. Although the precise mechanism how a single virus, TMEV, induces the distinct diseases in different organs is unclear, principal component analysis (PCA) of transcriptome data allows us to identify the key factors contributing to distinct immunopathology. The PCA demonstrated that in vitro infection of a cardiomyocyte cell line could reproduce the transcriptome profile of phase I in TMEV-induced myocarditis; distinct interferon/chemokine-related responses were induced in vitro in infected cardiomyocytes, but not in infected neuronal cells. In addition, the PCA of in vivo CNS transcriptome data showed that decreased lymphatic marker expression was associated with inflammation in TMEV infection. Here, dysfunction of lymphatic vessels may contribute to immunopathology by delaying clearance of cytokines and immune cells from the inflammatory site, although this might confine the virus at the site, preventing virus spread via lymphatic vessels. On the other hand, in the heart, dysfunction of lymphatics was associated with reduced lymphatic muscle contractility by pro-inflammatory cytokines. Therefore, TMEV infection could induce different cytokine expressions as well as lymphatic vessel dysfunction by the distinct mechanism between the CNS and heart, which might contribute to organ-specific immunopathology.
2019-04-23 | GSE119860 | GEO
Project description:Theiler’s murine encephalomyelitis virus (TMEV) induces different diseases in the central nervous system (CNS) and heart, depending on the mouse strains and time course, where cytokines play a key role for viral clearance and immune-mediated pathology (immunopathology). In SJL/J mice, TMEV infection causes chronic TMEV-induced demyelinating disease (TMEV-IDD) in the spinal cord around 1 month post infection (p.i.). Unlike other immunopathology models, both pro-inflammatory and anti-inflammatory cytokines can play dual roles in TMEV-IDD. Pro-inflammatory cytokines play a beneficial role in viral clearance while they also play a detrimental role in immune-mediated demyelination. Anti-inflammatory cytokines suppress not only protective anti-viral immune responses but also detrimental autoreactive immune responses. On the other hand, in C3H mice, TMEV infection induces a non-CNS disease, myocarditis, with three phases: phase I, viral pathology with interferon and chemokine responses; phase II, immunopathology mediated by acquired immune responses; and phase III, cardiac fibrosis. Although the precise mechanism how a single virus, TMEV, induces the distinct diseases in different organs is unclear, principal component analysis (PCA) of transcriptome data allows us to identify the key factors contributing to distinct immunopathology. The PCA demonstrated that in vitro infection of a cardiomyocyte cell line could reproduce the transcriptome profile of phase I in TMEV-induced myocarditis; distinct interferon/chemokine-related responses were induced in vitro in infected cardiomyocytes, but not in infected neuronal cells. In addition, the PCA of in vivo CNS transcriptome data showed that decreased lymphatic marker expression was associated with inflammation in TMEV infection. Here, dysfunction of lymphatic vessels may contribute to immunopathology by delaying clearance of cytokines and immune cells from the inflammatory site, although this might confine the virus at the site, preventing virus spread via lymphatic vessels. On the other hand, in the heart, dysfunction of lymphatics was associated with reduced lymphatic muscle contractility by pro-inflammatory cytokines. Therefore, TMEV infection could induce different cytokine expressions as well as lymphatic vessel dysfunction by the distinct mechanism between the CNS and heart, which might contribute to organ-specific immunopathology.
2019-04-23 | GSE120041 | GEO
Project description:Theiler’s Virus-Mediated Immunopathology in the CNS and Heart: Roles of Organ-Specific Cytokine and Lymphatic Responses [array]
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Project description:Theiler’s Virus-Mediated Immunopathology in the CNS and Heart: Roles of Organ-Specific Cytokine and Lymphatic Responses [RNA-Seq]
| PRJNA491437 | ENA
Project description:Theiler's murine encephalomyelitis virus (TMEV) induces different diseases in the central nervous system (CNS) and heart, depending on the mouse strains and time course, with cytokines playing key roles for viral clearance and immune-mediated pathology (immunopathology). In SJL/J mice, TMEV infection causes chronic TMEV-induced demyelinating disease (TMEV-IDD) in the spinal cord about 1 month post-inoculation (p.i.). Unlike other immunopathology models, both pro- and anti-inflammatory cytokines can play dual roles in TMEV-IDD. Pro-inflammatory cytokines play beneficial roles in viral clearance while they are also detrimental in immune-mediated demyelination. Anti-inflammatory cytokines suppress not only protective anti-viral immune responses but also detrimental autoreactive immune responses. Conversely, in C3H mice, TMEV infection induces a non-CNS disease, myocarditis, with three distinctive phases: phase I, viral pathology with interferon and chemokine responses; phase II, immunopathology mediated by acquired immune responses; and phase III, cardiac fibrosis. Although the exact mechanism(s) by which a single virus, TMEV, induces these different diseases in different organs is unclear, our bioinformatics approaches, especially principal component analysis (PCA) of transcriptome data, allow us to identify the key factors contributing to organ-specific immunopathology. The PCA demonstrated that in vitro infection of a cardiomyocyte cell line reproduced the transcriptome profile of phase I in TMEV-induced myocarditis; distinct interferon/chemokine-related responses were induced in vitro in TMEV-infected cardiomyocytes, but not in infected neuronal cells. In addition, the PCA of the in vivo CNS transcriptome data showed that decreased lymphatic marker expressions were weakly associated with inflammation in TMEV infection. Here, dysfunction of lymphatic vessels is shown to potentially contribute to immunopathology by delaying the clearance of cytokines and immune cells from the inflammatory site, although this can also confine the virus at these sites, preventing virus spread via lymphatic vessels. On the other hand, in the heart, dysfunction of lymphatics was associated with reduced lymphatic muscle contractility provoked by pro-inflammatory cytokines. Therefore, TMEV infection may induce different patterns of cytokine expressions as well as lymphatic vessel dysfunction by rather different mechanisms between the CNS and heart, which might explain observed patterns of organ-specific immunopathology.
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Project description:The meningeal lymphatic network—housed within the dural meninges surrounding the brain— is critical for cerebrospinal fluid (CSF) drainage. Through continuous brain interstitial fluid (ISF) mixing with CSF via the glymphatic system, this lymphatic network facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer’s disease (AD), attenuated meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins—including amyloid beta—in the CNS. Alleviating this age-related meningeal lymphatic dysfunction represents a promising therapeutic strategy to alleviate AD pathology. However, the mechanisms underlying this lymphatic decline remain elusive. Here we demonstrate that age-related alterations in meningeal immunity contribute to meningeal lymphatic impairment. Single-cell RNA-sequencing of dural lymphatic endothelial cells in aged mice demonstrated a response signature to the cytokine IFNγ, which was elevated in the aged dura due to meningeal T cell accumulation. Chronic elevation of IFNγ in the meninges of young mice via AAV-mediated overexpression altered lymphatic adherans junctions and impaired CSF drainage to deep cervical lymph nodes—comparable to the deficits observed in aged mice. Direct disruption of lymphatic junctions via CSF-delivered VE-Cadherin disrupting antibodies was sufficient to phenocopy impairments in CSF drainage. Therapeutically, IFNγ neutralization in aged mice alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable therapeutic target to normalize CSF drainage in aged mice and alleviate the pathology in AD mice associated with impaired waste removal.
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Project description:The meningeal lymphatic network—housed within the dural meninges surrounding the brain— is critical for cerebrospinal fluid (CSF) drainage. Through continuous brain interstitial fluid (ISF) mixing with CSF via the glymphatic system, this lymphatic network facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer’s disease (AD), attenuated meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins—including amyloid beta—in the CNS. Alleviating this age-related meningeal lymphatic dysfunction represents a promising therapeutic strategy to alleviate AD pathology. However, the mechanisms underlying this lymphatic decline remain elusive. Here we demonstrate that age-related alterations in meningeal immunity contribute to meningeal lymphatic impairment. Single-cell RNA-sequencing of dural lymphatic endothelial cells in aged mice demonstrated a response signature to the cytokine IFNγ, which was elevated in the aged dura due to meningeal T cell accumulation. Chronic elevation of IFNγ in the meninges of young mice via AAV-mediated overexpression altered lymphatic adherans junctions and impaired CSF drainage to deep cervical lymph nodes—comparable to the deficits observed in aged mice. Direct disruption of lymphatic junctions via CSF-delivered VE-Cadherin disrupting antibodies was sufficient to phenocopy impairments in CSF drainage. Therapeutically, IFNγ neutralization in aged mice alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable therapeutic target to normalize CSF drainage in aged mice and alleviate the pathology in AD mice associated with impaired waste removal.
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Project description:Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.
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2019-04-23 | GSE120042 | GEO
Project description:Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.
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