A gut-brain-body circuit mediates immune evasion in viral infection
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ABSTRACT:
PROVIDER: PRJNA1212042 | ENA |
REPOSITORIES: ENA
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Project description:The gut–brain axis plays an important role in regulating antiviral immunity through multiple pathways. However, the mechanisms by which these pathways respond to viral infections remain unclear. In this study, we found that mice without TRPV1+ neurons exhibited a diminished antiviral immune response. TRPV1+ neurons in the mediodorsal thalamic nucleus (MD) enhanced antiviral immune response. In addition, the administration of a TRPV1 agonist enhanced the antiviral immune response in mice, whereas a TRPV1 inhibitor suppressed such a response. Moreover, VGLUT2+TRPV1+ neurons rather than VGAT+TRPV1+ neurons played the pivotal role in antiviral immunity. We identified the bed nucleus of the stria terminalis (BST) and the dorsomedial hypothalamic nucleus (DMH) as downstream targets of the MD. Moreover, MD–BST axis facilitated the release of substance P (SP) and calcitonin gene-related peptide (CGRP) from the brain into the cerebrospinal fluid, which then entered the bloodstream to potentiate the antiviral response in macrophages. Mechanistically, SP and CGRP enhanced the type-I interferon production via the PKA-STING and PKC-IRF3 pathways, respectively. Furthermore, viral infection triggered the production of gut microbiota–derived desthiobiotin, which reduced TRPV1 expression in the MD, thereby promoting immune evasion. Notably, the desthiobiotin inhibitor ML406 enhanced antiviral immunity and blocked immune evasion. These findings provide new insights into the mechanism by which viruses regulate the gut–brain–body axis and unveil a novel immune evasion strategy with substantial implications for developing antiviral therapies.
2025-02-01 | GSE287291 | GEO
Project description:A body-brain circuit regulating body inflammatory responses
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Project description:The body-brain axis is emerging as a principal conductor of organismal physiology. It senses and controls organ function, metabolism and nutritional state. Here, we show that a peripheral immune insult powerfully activates the body-brain axis to regulate immune responses. We demonstrate that pro- and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body-to-brain circuit produced unregulated and out-of-control inflammatory responses. By contrast, activating, rather than silencing, this circuit affords exceptional neural control of immune responses. We used single-cell RNA sequencing, combined with functional imaging, to identify the circuit components of this neuro-immune axis, and showed that its selective manipulation can effectively suppress the pro-inflammatory response while enhancing an anti-inflammatory state. The brain-evoked transformation of the course of an immune response offers new possibilities in the modulation of a wide range of immune disorders, from autoimmune diseases to cytokine storm and shock.
2024-04-11 | GSE263025 | GEO
Project description:Glycosphingolipid synthesis mediates immune evasion in Kras-driven cancer
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Project description:Here, we demonstrated the neurotropism of different retrograde viral tracers are distinct through parallel comparison of multi-synaptic and mono-synaptic tracers in circuit tracing. By virture of their distinct tropism, we reconstructed more comprehensive LHA input circuit map. Notably, exogenous expression of TVA receptor in rabies virus (RV) resistant neurons can enable the infection of EnVA-pseudotyped RV. The potential viral receptor candidates attributing to neurotropism were analyzed by single cell sequencing. Further, we systematically compared neurotoxicity of glycoprotein-deleted RV and rAAV2-retro by RNAseq and immunohistochemistry. Finally, we demonstrated a proof-of-concept strategy for high-order circuit tracing by combining different viral tracers.
2018-06-23 | GSE115865 | GEO
Project description:Viral infection makes us feel sick. The extent of these changes to our metabolism are relative to the severity of disease. Whether blood glucose levels are subject to infection-induced modulation is largely unknown. Here we show that strong, non-lethal infection restricts systemic glucose availability which promotes the antiviral IFN-I response. Following systemic viral infection of mice, we find that IFNγ produced by γδ T cells directly stimulates pancreatic β-cells to increase glucose-induced insulin release. Subsequently, hyperinsulinemia lessens endogenous glucose output by the liver. Glucose restriction enhances type-I interferon production by curtailing lactate-mediated inhibition of IRF3 and NF-κB signaling. Induced hyperglycemia constrained IFN-I production and increased mortality upon infection. Our findings identify glucose restriction as a physiological mechanism to bring the body into a heightened state of responsiveness to viral pathogens. This immune-endocrine circuit is disrupted in hyperglycemia, which explains why patients with metabolic disease are more susceptible to viral infection.
2024-04-14 | GSE263599 | GEO
Project description:Viral infection makes us feel sick. The extent of these changes to our metabolism are relative to the severity of disease. Whether blood glucose levels are subject to infection-induced modulation is largely unknown. Here we show that strong, non-lethal infection restricts systemic glucose availability which promotes the antiviral IFN-I response. Following systemic viral infection of mice, we find that IFNγ produced by γδ T cells directly stimulates pancreatic β-cells to increase glucose-induced insulin release. Subsequently, hyperinsulinemia lessens endogenous glucose output by the liver. Glucose restriction enhances type-I interferon production by curtailing lactate-mediated inhibition of IRF3 and NF-κB signaling. Induced hyperglycemia constrained IFN-I production and increased mortality upon infection. Our findings identify glucose restriction as a physiological mechanism to bring the body into a heightened state of responsiveness to viral pathogens. This immune-endocrine circuit is disrupted in hyperglycemia, which explains why patients with metabolic disease are more susceptible to viral infection.
2024-04-14 | GSE263600 | GEO
Project description:Epigenetic therapies that alter DNA- and/or histone modifications facilitate transcription of immunogenic repetitive elements that cull cancer cells through ‘viral mimicry’ responses. Paradoxically, cancer-initiating events that include functional inactivation of canonical tumor suppressor proteins also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize patient-derived premalignant lesions of the fallopian tube along with syngeneic mouse models of epithelial ovarian cancer to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss disrupts constitutive heterochromatin to permit transcription of immunogenic repetitive elements capable of activating viral mimicry responses. While acute viral mimicry activation diminishes cell fitness, chronic viral mimicry activation following p53 loss promotes epigenetic reprogramming that increases tolerance of cytosolic nucleic acids and diminishes cellular immunogenicity as a pro-survival adaptation. This selection process we describe as ‘viral mimicry conditioning’ can be partially attenuated by the reverse transcriptase inhibitor 3TC to delay spontaneous tumorigenesis. Altogether, these results reveal that viral mimicry conditioning following p53 loss selects for diminished cell immunogenicity to promote immune evasion upon cancer initiation. Disruption of viral mimicry conditioning during cancer initiation may represent a pharmacological target for early cancer interception.
2024-12-10 | GSE216640 | GEO
Project description:Epigenetic therapies that alter DNA- and/or histone modifications facilitate transcription of immunogenic repetitive elements that cull cancer cells through ‘viral mimicry’ responses. Paradoxically, cancer-initiating events that include functional inactivation of canonical tumor suppressor proteins also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize patient-derived premalignant lesions of the fallopian tube along with syngeneic mouse models of epithelial ovarian cancer to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss disrupts constitutive heterochromatin to permit transcription of immunogenic repetitive elements capable of activating viral mimicry responses. While acute viral mimicry activation diminishes cell fitness, chronic viral mimicry activation following p53 loss promotes epigenetic reprogramming that increases tolerance of cytosolic nucleic acids and diminishes cellular immunogenicity as a pro-survival adaptation. This selection process we describe as ‘viral mimicry conditioning’ can be partially attenuated by the reverse transcriptase inhibitor 3TC to delay spontaneous tumorigenesis. Altogether, these results reveal that viral mimicry conditioning following p53 loss selects for diminished cell immunogenicity to promote immune evasion upon cancer initiation. Disruption of viral mimicry conditioning during cancer initiation may represent a pharmacological target for early cancer interception.
2024-12-10 | GSE216941 | GEO
Project description:Chronic viral mimicry induction following p53 loss promotes immune evasion
| PRJNA896220 | ENA