Age-dependent differences in the immune response to human metapneumovirus

对人类偏肺病毒的免疫反应存在年龄依赖性差异

• 批准号: 10700837
• 负责人: Olivia Parks
• 金额: $ 4.94万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-08-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700837
• 关键词: 2019-nCoV; Adoptive Transfer; Age; Alveolar Macrophages; Bioinformatics; Biological Assay; Body Weight decreased; Bone Marrow; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Communication; Cells; Chest; Child; Chimera organism; Clinical; Coculture Techniques; Color; Communicable Diseases; Data; Development; Dichloromethylene Diphosphonate; Disease; Elderly; Epigenetic Process; Exhibits; Flow Cytometry; Functional disorder; Funding; Genes; Genetic Transcription; Goals; Hospitalization; Human Metapneumovirus; Immune; Immune response; Immunity; Immunocompromised Host; Immunologics; Immunology; Impairment; In Vitro; Infection; Inflammatory; Influenza; Isogenic transplantation; Knowledge; Label; Laboratories; Liposomes; Literature; Longevity; Lower Respiratory Tract Infection; Lung; Macrophage; Mediator; Molecular Target; Morbidity - disease rate; Mus; Natural Immunity; Neonatal; Pathogenesis; Pathway interactions; Persons; Population; Populations at Risk; Predisposition; Prevention; Primary Infection; Principal Investigator; Pulmonary Inflammation; Reporting; Research; Research Personnel; Respiratory Disease; Respiratory Tract Infections; Respiratory syncytial virus; Role; Scientist; Seasons; Severities; Severity of illness; Signal Transduction; T cell response; T-Lymphocyte; Technical Expertise; Testing; Tissues; Training; Translating; Vaccines; Viral; Virus; Virus Replication; Vulnerable Populations; Weight Gain; Western Blotting; adaptive immunity; age related; aged; candidate identification; career; cell type; chromatin modification; clinical translation; cytokine; experimental study; functional disability; immunoregulation; improved; monocyte; mortality; mouse model; multiple omics; neutralizing antibody; novel; prevent; programmed cell death protein 1; reconstitution; respiratory; respiratory pathogen; respiratory virus; secondary infection; secondary lymphoid organ; skills; tool; training opportunity

ABSTRACT Human metapneumovirus (HMPV) is a leading cause of lower respiratory infections in young children, immunocompromised persons, and the elderly, resulting in high morbidity and mortality. Few studies have investigated why HMPV is more severe in the elderly. This proposal aims to fill this knowledge gap about HMPV pathogenesis. My preliminary data discovered that aged mice infected with HMPV exhibit delayed viral clearance, increased lung inflammation, and increased CD8+ HMPV-tetramer+ cells co-expressing the inhibitory markers PD-1, TIM-3, and LAG-3. I hypothesize that severe HMPV infection in the elderly is caused by impairment of the CD8+ T cell response. In Aim 1, I will investigate the intrinsic causes of the CD8+ T cell impairment observed in the aged host infected with HMPV using 10X Multiomics studies on murine lung directly ex vivo and syngeneic transplants. 10X Multiomics will elucidate age-related epigenetic changes in CD8+ T cells while syngeneic transplants will transfer young CD8+ T cells into an aged host and vice versa to determine if CD8+ T cells are the primary immune cells causing the impaired immune response to HMPV (i.e. increased weight loss, clinical severity, delayed viral clearance). In Aim 2, I will investigate extrinsic causes of the CD8+ T cell impairment, namely by alveolar macrophages (AMs). I will use a 21-color multispectral flow cytometry panel to enumerate M1 and M2 macrophage populations in the aged host. In vitro co-culture and transwell assays of AMs and CD8+ T cells will determine if AMs directly impair CD8+ T cells. Selective depletion of AMs in aged mice and adoptive transfer of young macrophages will determine how AMs contribute to the impaired immune response in the aged host. 10X Multiomics will also be performed in this aim to investigate the age-related epigenetic changes in AMs that may contribute to their aberrant M2 accumulation, which I have also observed in my preliminary data. This proposal aims to understand the mechanistic differences in the aged host response to HMPV, which will help elucidate why HMPV infection in the elderly is more severe. These studies have the potential to translate into the clinical setting and contribute to better management and treatment for HMPV infection, such as immunomodulation. Identifying molecular targets in the aged host will guide development of a safe and effective vaccine against HMPV for all at-risk populations. In addition, this proposal has tremendous training opportunities, contributing towards my career goals of becoming a clinician scientist and independent principal investigator in immunology and infectious disease.

抽象的 人类偏肺病毒（HMPV）是幼儿下呼吸道感染的主要原因， 免疫功能低下者和老年人，导致高发病率和死亡率。很少有研究表明 研究了为什么 HMPV 在老​​年人中更为严重。该提案旨在填补这一知识空白 HMPV 发病机制。我的初步数据发现，感染 HMPV 的老年小鼠表现出延迟病毒 清除率、肺部炎症增加以及共表达 CD8+ HMPV-四聚体+细胞增加 抑制标记物 PD-1、TIM-3 和 LAG-3。我推测老年人严重的 HMPV 感染是 由 CD8+ T 细胞反应受损引起。在目标 1 中，我将调查造成这种情况的内在原因。 使用 10X 小鼠多组学研究在感染 HMPV 的老年宿主中观察到 CD8+ T 细胞损伤 肺直接离体移植和同基因移植。 10X Multiomics 将阐明与年龄相关的表观遗传变化 CD8+ T 细胞，而同基因移植将年轻的 CD8+ T 细胞转移到老年宿主中，反之亦然 确定 CD8+ T 细胞是否是导致 HMPV 免疫反应受损的主要免疫细胞（即 体重减轻增加、临床严重程度增加、病毒清除延迟）。在目标 2 中，我将调查外在原因 CD8+ T 细胞损伤，即肺泡巨噬细胞 (AM) 损伤。我将使用 21 色多光谱流 细胞计数板可计数老年宿主中的 M1 和 M2 巨噬细胞群。体外共培养和 AM 和 CD8+ T 细胞的 Transwell 检测将确定 AM 是否直接损害 CD8+ T 细胞。选择性耗尽 老年小鼠中的 AMs 和年轻巨噬细胞的过继转移将决定 AMs 如何促进 老年宿主的免疫反应受损。为此目的，还将进行 10X 多组学研究 AMs 中与年龄相关的表观遗传变化可能导致其异常的 M2 积累，我有 在我的初步数据中也观察到。 该提案旨在了解老年宿主对 HMPV 反应的机制差异， 这将有助于阐明为什么老年人中HMPV感染更为严重。这些研究有潜力 转化为临床环境并有助于更好地管理和治疗 HMPV 感染，例如 作为免疫调节。识别老年宿主的分子靶标将指导开发安全且可靠的药物 为所有高危人群提供有效的 HMPV 疫苗。 此外，该提案还有大量的培训机会，有助于实现我的职业目标 成为免疫学和传染病领域的临床科学家和独立首席研究员。