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T cell/astrocyte fusions as a novel form of trained immunity to infection

T 细胞/星形胶质细胞融合作为一种新型的感染免疫训练形式

基本信息

批准号：
10723089
负责人：
E. Ashley Moseman
金额：
$ 23.72万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10723089
关键词：
Adoptive Transfer Animal Model Animals Antigen Presentation Astrocytes Biological Biology Brain CD8-Positive T-Lymphocytes COVID-19 Cell fusion Cell hybridization Cells Cellular Immunology Cellular Structures Cellular Tropism Central Nervous System Central Nervous System Infections Central Nervous System Viral Diseases Chronic Cytoprotection Detection Disparate Encephalitis Gene Expression Generations Genetic Genetic Materials Genetic Transcription Genome Health Hematopoietic Homeostasis Human Hybrid Cells Hybrids Image Immune Immune response Immunity Immunologics Impaired cognition Infection Infiltration Inflammation Inflammatory Influenza Invaded Kinetics Longevity Lymphocyte Memory Modeling Mus Nerve Degeneration Neuroglia Neurons Pathologic Process RNA Viruses Reporter Respiratory Tract Infections Role Source Symptoms System T-Lymphocyte Testing Training Transgenic Organisms Upper Respiratory Infections Vesicular stomatitis Indiana virus Viral Viral Antigens Virus Virus Diseases brain fog cell type cognitive change driving force histological studies human pathogen hybrid gene insight neuroprotection novel olfactory sensory neurons pandemic disease recruit tissue resident memory T cell transcriptome sequencing transcriptomics

项目摘要

Abstract: Could fusion between two disparate cell types generate an unconventional memory of infection? Would this hybrid cell protect against tomorrow’s pandemics or promote neurodegeneration and cognitive decline? In virally infected mice, we serendipitously discovered the presence of long-lived cellular fusions between astrocytes, a major glial cell type in the central nervous system (CNS), and antiviral CD8+ T lymphocytes (T cells), which infiltrate the CNS following an upper airway infection. Remarkably, these T cell/astrocyte hybrids retain the cellular structure of an astrocyte but maintain gene expression only present in the T cell genome. While tissue- resident memory T cells are known to remain in the CNS after infection, T cell/astrocyte fusions represent an entirely novel cell fate that we consistently observe. This suggests that the transfer of genetic material from T cells could represent a widespread phenomenon associated with astrocyte reactivity. Histological studies of human brains have described hematopoietic fusions within the CNS, particularly in inflammatory settings, but the driving forces, mechanisms, and implications are unknown. Human pathogens, including those that cause upper respiratory infections (URI), directly infect or impact the CNS with symptoms ranging from mild inflammation to overt encephalitis and have been associated with cognitive changes and neurodegeneration, including “brain fog” associated with Influenza and Covid-19. These varying impacts on brain function are likely multifactorial but regional alterations in CNS gene expression are readily observed in animal models. We hypothesize that T cell/astrocyte hybrids represent a novel cell type possessing an engrained memory of inflammation that contributes to inflammatory and neurodegenerative processes. We will establish parameters that govern astrocyte and T cell hybrid formation and identify a core signature and biological consequences of infection-driven cell hybridization on inflammatory and immune processes.

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