MAVS signaling shapes microglia responses to neurotropic virus infection
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ABSTRACT:
PROVIDER: PRJNA1148457 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30252106_1.fastq.gz | Fastqsanger.gz | |||
| SRR30252106_2.fastq.gz | Fastqsanger.gz | |||
| SRR30252107_1.fastq.gz | Fastqsanger.gz | |||
| SRR30252107_2.fastq.gz | Fastqsanger.gz | |||
| SRR30252108_1.fastq.gz | Fastqsanger.gz |
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Project description:Viral encephalitis is characterized by a series of immunological reactions that can control virus infection in the brain, but dysregulated responses may cause excessive inflammation and brain damage. Microglia are brain-resident myeloid cells that are specialized on surveillance of the local environment and in case of viral brain infection they contribute to control of the infection and restriction of viral dissemination. Here, we report that after exposure to neurotropic vesicular stomatitis virus (VSV), murine in vitro microglia cultures showed rapid upregulation of a broad range of pro-inflammatory and antiviral genes, which were stably expressed over the entire 8 hours infection period. Additionally, a set of immunomodulatory genes was upregulated between 6 and 8 hours post infection. In in vitro microglia, the induction of several immune response pathways including cytokine responses was dependent on mitochondrial antiviral-signaling protein (MAVS). Consequently, in Mavs-deficient microglia control of virus infection failed as indicated by augmented accumulation of viral transcripts. Thus, in the analyzed in vitro system, MAVS signaling is critically required to achieve full microglia activation and to mediate profound antiviral effects. In Mavs-deficient mice, intranasal VSV instillation caused higher disease severity than in WT mice and the virus disseminated beyond the olfactory bulb and entered more distal brain regions. Virus spread to inner regions of the olfactory bulb, i.e., the granular cell layer, correlated with infiltration of highly inflammatory non-microglial myeloid cells into the olfactory bulb. Furthermore, increased cytokine levels were detected in the nasal cavity, the olfactory bulb and in other brain regions. Thus, microglial MAVS signaling is critically needed for virus sensing, full microglia activation, and for orchestration of protective immunity in the virus-infected CNS.
2024-08-29 | GSE274915 | GEO
Project description:Viral encephalitis is characterized by a series of immunological reactions that can control virus infection in the brain, but dysregulated responses may cause excessive inflammation and brain damage. Microglia are brain-resident myeloid cells that are specialized in surveilling the local CNS environment and in case of viral brain infection they contribute to the control of the infection and to restriction of viral dissemination. Here, we report that after exposure to neurotropic vesicular stomatitis virus (VSV), murine in vitro microglia cultures showed rapid upregulation of a broad range of pro-inflammatory and antiviral genes, which were stably expressed over the entire 8 h infection period. Additionally, a set of immunomodulatory genes was upregulated between 6 and 8 h post infection. In microglia cultures, the induction of several immune response pathways including cytokine responses was dependent on mitochondrial antiviral-signaling protein (MAVS). Consequently, in Mavs-deficient microglia the control of virus propagation failed as indicated by augmented virus titers and the accumulation of viral transcripts. Thus, in the analyzed in vitro system, MAVS signaling is critically required to achieve full microglia activation and to mediate profound antiviral effects. In Mavs-deficient mice, intranasal VSV instillation caused higher disease severity than in WT mice and virus dissemination was noticed beyond the olfactory bulb. Virus spread to inner regions of the olfactory bulb, i.e., the granular cell layer, correlated with the recruitment of highly inflammatory non-microglia myeloid cells into the olfactory bulb in Mavs-/- mice. Furthermore, increased cytokine levels were detected in the nasal cavity, the olfactory bulb and in other brain regions. Thus, microglial MAVS signaling is critically needed for virus sensing, full microglia activation, and for orchestration of protective immunity in the virus-infected CNS.
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Project description:Goal: Determine the role of microglia in the antiviral response during neurotropic picornavirus infection of C57BL/6J and SJL/J mice and whether absence of microglia would affect CD4 and CD8 T cell functions. Methods: Brains from C57BL/6J and SJL/J mice treated with PLX5622 (to deplete microlgia) or control diet were harvested at 6 days post TMEV-infection. CD4+ T cells and CD8+ T cells were obtained using Easy Sep Mouse CD4+ T cell isolation Kit and Easy Sep Mouse CD8+ T cell isolation Kit (Stemcell). RNA was obtained using RNeasy (QIAGEN) and Illumina TruSeq stranded RNA Kit with Ribo-Zero Gold was then utilized to prepare cDNA library for RNA-seq. Results: Our results demonstrate strain-specific effects of the CSF1R-microglia axis in the context of neurotropic viral infection as well as inherent differences in microglial antigen presentation and subsequent T cell crosstalk that contribute to susceptibility to neurotropic picornavirus infection.
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Project description:Neurotropic viruses like vesicular stomatitis virus (VSV) can infect the central nervous system (CNS) through the olfactory route. Following intranasal instillation, VSV moves along the axons of olfactory sensory neurons to the olfactory bulb. While within the olfactory bulb the spread of the virus is controlled by microglia activation and the recruitment of peripheral leukocytes, some of the underlying mechanisms remain unknown. To investigate these mechanisms, we used mice with conditional deletions of the mitochondrial antiviral-signaling protein (MAVS), an adaptor for RIG-I-like receptor (RLR)-signaling. By selectively deleting MAVS in neurons, astrocytes, or long-lived myeloid cells, we discovered that RLR-signaling specifically within brain-resident myeloid cells is crucial for protection against the virus. Mice with a MAVS deletion in these myeloid cells showed normal myeloid cell and leukocyte infiltration into the brain. However, the P2RY12+ microglia showed aberrant expression of genes involved in antigen cross-presentation.Furthermore, flow cytometry experiments revealed diminished MHC class I expression on MAVS deficient microglia. Moreover, CNS-infiltrating CD8+T cells had dysfunctional transcriptional profiles. Therefore, our findings indicate that during viral CNS infection, MAVS signaling in brain-resident myeloid cells, presumably microglia, is essential for antigen cross-presentation and the relicensing of protective, infiltrating CD8+ T cells.
2025-07-07 | GSE301540 | GEO
Project description:Neurotropic viruses like vesicular stomatitis virus (VSV) can infect the central nervous system (CNS) through the olfactory route. Following intranasal instillation, VSV moves along the axons of olfactory sensory neurons to the olfactory bulb. While within the olfactory bulb the spread of the virus is controlled by microglia activation and the recruitment of peripheral leukocytes, some of the underlying mechanisms remain unknown. To investigate these mechanisms, we used mice with conditional deletions of the mitochondrial antiviral-signaling protein (MAVS), an adaptor for RIG-I-like receptor (RLR)-signaling. By selectively deleting MAVS in neurons, astrocytes, or long-lived myeloid cells, we discovered that RLR-signaling specifically within brain-resident myeloid cells is crucial for protection against the virus. Mice with a MAVS deletion in these myeloid cells showed normal myeloid cell and leukocyte infiltration into the brain. However, the P2RY12+ microglia showed aberrant expression of genes involved in antigen cross-presentation.Furthermore, flow cytometry experiments revealed diminished MHC class I expression on MAVS deficient microglia. Moreover, CNS-infiltrating CD8+T cells had dysfunctional transcriptional profiles. Therefore, our findings indicate that during viral CNS infection, MAVS signaling in brain-resident myeloid cells, presumably microglia, is essential for antigen cross-presentation and the relicensing of protective, infiltrating CD8+ T cells.
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Project description:Ischemic stroke (IS) is one of the most serious neurological diseases, characterized by high mortality and disability rates. Glia cells, particularly microglia and astrocytes, occupy a pivotal position in the progression of IS. In response to stroke, microglia undergo polarization, transforming into either pro-inflammatory M1 phenotype or anti-inflammatory M2 phenotype. Analogously, astrocytes would polarize to pro-inflammatory A1 phenotype or anti-inflammatory A2 phenotype. It has been documented that A1 astrocytes can be activated by M1 microglia, although precise underlying mechanism remains elusive. In our study, we emulated ischemic injury using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in mice and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in primary astrocytes. Our findings revealed that M1 microglia could activate A1 astrocytes by secreting exosomes. According to RNA sequencing, circSTRN3 was enriched in M1 microglia-derived exosomes. Based on the review of literature and bioinformatics analysis, it was suggested that circSTRN3 could sponge miR-331-5p, while miR-331-5p could bind to MAVS and participate in the activation of NF-kB pathway and A1 astrocytes. Western blotting and qRT-PCR experiments verified this process. Furtherly, overexpression of circSTRN3 could aggravate neurological deficits, increase infarct volume, and promote cell death in MCAO/R model, whereas miR-331-5p inhibited this process. Furthermore, we conducted tests on circSTRN3 and miR-331-5p in exosomes isolated from the peripheral blood of IS patients, thereby confirming the correlation among circSTRN3, miR-331-5p, and the stroke severity score. Taken together, our study indicated that M1 microglia-derived exosomes could promote A1 astrocyte activation and exacerbate ischemic brain injury through the circSTRN3-miR331-5P/MAVS/NF-KB pathway.
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Project description:Upon tick borne encephalitis virus exposure of brain-resident cells, astrocytes are important IFN-β producers that followed a biphasic response, which initially depends on MAVS- and later on MyD88/TRIF-signaling
2021-09-28 | GSE175823 | GEO
Project description:Epstein-Barr virus (EBV) causes infectious mononucleosis, triggers multiple sclerosis and is associated with 200,000 cancers/year. EBV colonizes the B-cell compartment and periodically reactivates, inducing expression of 80 viral proteins. Yet much remains unknown about how EBV remodels host cells and dismantles key antiviral responses. We therefore created a proteomic map of EBV-host and EBV-EBV interactions in B-cells undergoing EBV replication, uncovering conserved herpesvirus versus EBV-specific host cell targets. The EBV-encoded G-protein coupled receptor BILF1 associated with MAVS and the UFM1 E3 ligase UFL1. Whereas UFMylation of 14-3-3 proteins drives RIG-I/MAVS signaling, BILF1-directed MAVS UFMylation instead triggered MAVS packaging into mitochondrial-derived vesicles and lysosomal proteolysis. In the absence of BILF1, EBV replication activated the NLRP3 inflammasome, which impaired viral replication and triggered pyroptosis. Our results provide a viral protein interaction network resource, reveal a UFM1-dependent pathway for selective degradation of mitochondrial cargo and highlight BILF1 as a novel therapeutic target.
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