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Molecular pathology of anti-viral T cell responses in the central nervous system

Project description

Molecular aetiology of immune responses in the CNS

Immune responses against viruses in the central nervous system (CNS) can disrupt neuronal homeostasis and cause permanent damage. The EU-funded PATHOCODE project is investigating the mechanisms by which non-cytolytic CD8+ T cells affect infected as well as non-infected neurons in the CNS. Using a unique animal model of T cell-driven virus encephalitis, scientists will study the epigenetic and downstream metabolic changes induced in infected neurons by T cell immune responses. The project's findings will decipher the molecular aetiology of neuronal dysfunction in CNS inflammatory diseases and identify potential targets for therapeutic intervention.

Objective

"Immune responses against viruses in the central nervous system (CNS) can result in devastating outcomes. Even non-cytolytic CD8+ T cell interactions, which purge viruses from neurons without triggering cell death, can induce permanent damage. Yet, how this immune response irreversibly disrupts neuronal homeostasis remains unclear.
Here, we will elucidate the molecular mechanisms that underlie non-cytolytic CD8+ T cell engagement with infected neurons and their consequences on neuron function in vivo. We hypothesize that inflammatory signalling in neurons, induced by non-cytolytic CD8+ T cell interactions, triggers metabolic and epigenetic changes that underpin permanent neuronal dysfunction.
""PATHOCODE"" will test this hypothesis by harnessing a unique animal model of T cell-driven virus encephalitis in the following objectives: 1. Discern neuronal subset-specific vulnerabilities and antigen-dependent versus bystander effects in the inflamed CNS. We will perform single nucleus RNA sequencing to examine whether T cell engagement (a) differentially affects molecularly distinct neurons, and (b) affects non-targeted, uninfected neurons. 2. Uncover the consequences of non-cytolytic T cell engagement on neuronal metabolism. We will use cell-specific mitochondrial reporter mice to investigate immune-driven metabolic adaptation of neurons in vivo. 3. Determine how non-cytolytic T cell engagement affects the neuronal epigenome. We will employ cell-specific nucleus/ribosome reporter mice to elucidate how T cell engagement affects the translatome and epigenome of infected cells. 4. Rescue T cell-mediated neuronal dysfunction by restoring metabolic pathways. We will exploit recent CRISPR/Cas9 technological advances to restore neuronal gene expression and uncover the relevance of immune-driven metabolic and epigenomic changes to disease. Our study will thus provide novel molecular concepts about immune-driven neuronal alterations in CNS inflammatory diseases."

Fields of science (EuroSciVoc)

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Host institution

UNIVERSITE DE GENEVE
Net EU contribution
€ 1 999 954,00
Address
RUE DU GENERAL DUFOUR 24
1211 Geneve
Switzerland

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Region
Schweiz/Suisse/Svizzera Région lémanique Genève
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 1 999 954,00

Beneficiaries (1)