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

• 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
• 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

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.

抽象的： 两种不同细胞类型之间的融合是否会产生非常规的感染记忆？这会吗 混合细胞可以预防未来的流行病还是促进神经退行性变和认知能力下降？在病毒式传播中 在被感染的小鼠中，我们偶然发现星形胶质细胞之间存在长寿命的细胞融合， 中枢神经系统 (CNS) 中的主要胶质细胞类型和抗病毒 CD8+ T 淋巴细胞 (T 细胞)， 上呼吸道感染后浸润中枢神经系统。值得注意的是，这些 T 细胞/星形胶质细胞杂交体保留了 星形胶质细胞的细胞结构，但维持仅存在于 T 细胞基因组中的基因表达。而组织- 众所周知，常驻记忆 T 细胞在感染后仍保留在 CNS 中，T 细胞/星形胶质细胞融合代表了一种 我们一直观察到全新的细胞命运。这表明遗传物质从T 细胞可能代表与星形胶质细胞反应性相关的普遍现象。组织学研究 人类大脑已经描述了中枢神经系统内的造血融合，特别是在炎症环境中，但是 驱动力、机制和影响尚不清楚。人类病原体，包括那些导致 上呼吸道感染 (URI)，直接感染或影响中枢神经系统，症状从轻微到 炎症到明显的脑炎，并与认知变化和神经退行性变有关， 包括与流感和 Covid-19 相关的“脑雾”。这些对大脑功能的不同影响可能是 在动物模型中很容易观察到中枢神经系统基因表达的多因素但区域性的变化。我们 假设 T 细胞/星形胶质细胞杂交代表了一种新的细胞类型，具有根深蒂固的记忆 导致炎症和神经退行性过程的炎症。我们将建立参数 控制星形胶质细胞和 T 细胞杂交形成并确定其核心特征和生物学后果 感染驱动的细胞杂交对炎症和免疫过程的影响。