IL-17 regulation of type-1 immunity in chronic viral infection

IL-17 对慢性病毒感染中 1 型免疫的调节

• 批准号: 10641910
• 负责人: Mandy J McGeachy
• 金额: $ 42.79万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-10 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641910
• 关键词: Adoptive Transfer; Antibodies; Antiviral Response; Attention; Automobile Driving; Bacteria; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Count; Cell Proliferation; Cell Survival; Cell physiology; Cells; Chronic; Chronic Phase; Clinical; Data; Development; Elements; Future; Gene Expression Profiling; Genes; Genetic; HIV; Hepatitis B; IL17 gene; Immune; Immune response; Immunity; Immunosuppression; Infection; Inflammation; Inflammatory Response; Interferon Type II; Invaded; Kinetics; Lead; Lymphocytic choriomeningitis virus; Lymphoid; Lymphoid Tissue; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Modeling; Molecular Profiling; Morbidity - disease rate; Mus; Outcome; Pathology; Pathway interactions; Persons; Population; Production; Proliferating; Regulation; Regulatory T-Lymphocyte; Reticular Cell; Risk; Role; Signal Transduction; Source; Stromal Cells; Surface; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Time; Viral; Virus; Virus Diseases; antiviral immunity; cellular targeting; chronic autoimmune disease; chronic infection; design; exhaustion; extracellular; fungus; immunopathology; immunoregulation; improved; microbiota; novel; pathogen; response; tissue repair

ABSTRACT Viruses that successfully evade clearance without killing the host establish chronic infection. However, unresolved low-grade inflammation causes morbidity over time, including development of cancers. How to appropriately modulate immune responses to chronic infection without further damaging the host represents a major clinical challenge. Type-17 immunity is invoked by extracellular bacteria and fungi to control resident microbiota and invading pathogens at barrier surfaces, and to promote tissue repair. Th17 cells have received much attention as drivers of inflammation in chronic autoimmune diseases. However, there are sparse data regarding the role of type-17 responses in response to viral infection. Here we have employed the well-characterized model infection, LCMV clone 13, to test the role of IL-17 during chronic viral infection. IL-17 was increased systemically during the switch to the chronic phase of infection. Using genetic and antibody-mediated blockade of IL-17, our data unexpectedly reveal that IL-17 regulates Th1 and CD8+ T cell activation, exhaustion and immunopathology during LCMV infection. We have identified lymphoid stromal cells known as fibroblastic reticular cells (FRC) as key intermediaries of IL-17 effects in secondary lymphoid tissues. Gene expression analysis and antibody-mediated blockade support a role for excess IFNg in driving T cell exhaustion and immunopathology. These unexpected findings lead to our central hypothesis that IL-17 has an immunoregulatory role during chronic infection by limiting antiviral T cell IFNg-mediated exhaustion and immunopathology. This project is designed to dissect the key elements that we have identified to be required in this unexplored immunoregulatory pathway in chronic infection by probing the source of critical IL-17 (aim 1), LN stromal cells as targets of IL-17 (aim 2) and IFNg-mediated effects on exhaustion and immunopathology in absence of IL-17 signaling (aim 3). Together these data will define a novel and previously unexplored axis operating through IL-17 signaling in stromal cells to regulate IFNg- mediated pathology, revealing new opportunities for future therapeutic intervention in chronically infected people.

摘要 成功逃避清除而不杀死宿主的病毒建立慢性感染。 然而，未解决的低度炎症随着时间的推移会导致发病，包括发展 癌症。如何适当地调节对慢性感染的免疫反应，而不进一步 损害宿主代表了主要的临床挑战。第17类豁免是由 细胞外细菌和真菌，以控制屏障处的常驻微生物群和入侵病原体 表面，并促进组织修复。Th 17细胞作为免疫调节的驱动因子受到了广泛的关注。 慢性自身免疫性疾病中的炎症。然而，关于这一作用的数据很少。 对病毒感染的17型反应。在这里，我们使用了特征良好的 模型感染，LCMV克隆13，以测试IL-17在慢性病毒感染期间的作用。IL-17是 在向慢性感染阶段转变期间全身性增加。利用基因和 抗体介导的IL-17的阻断，我们的数据出乎意料地揭示了IL-17调节Th 1， LCMV感染过程中的CD 8 + T细胞活化、耗竭和免疫病理学我们有 发现淋巴基质细胞称为成纤维网状细胞（FRC）作为关键中介 IL-17在次级淋巴组织中的作用。基因表达分析和抗体介导的 阻断支持过量IFNg在驱动T细胞耗竭和免疫病理学中的作用。这些 意想不到的发现导致我们的中心假设，即IL-17在免疫调节过程中具有免疫调节作用。 通过限制抗病毒T细胞IFN-γ介导的耗竭和免疫病理学慢性感染。这 项目旨在剖析我们已经确定的在这方面所需的关键要素， 通过探索关键IL-17的来源来探索慢性感染中未探索的免疫调节途径 (aim 1）、LN基质细胞作为IL-17的靶点（目的2）和IFNg介导的对衰竭和 在不存在IL-17信号传导的情况下的免疫病理学（目的3）。这些数据将共同定义一个新的 以及先前未探索的轴通过基质细胞中的IL-17信号传导来调节IFNg-1。 介导的病理学，揭示了未来治疗干预慢性 感染者。