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 人元病毒（HMPV）是幼儿下呼吸道感染的主要原因， 免疫功能低下的人和老年人，导致高发病和死亡率。很少有研究 研究了为什么HMPV在老年人中更为严重。该建议旨在填补有关此知识的差距 HMPV发病机理。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，肺部炎症增加，CD8+ HMPV四聚体+细胞共表达 抑制标记PD-1，TIM-3和LAG-3。我假设老年人的严重HMPV感染是 由CD8+ T细胞反应受损引起。在AIM 1中，我将研究 使用10倍多组学研究的鼠类感染了HMPV的老年宿主在老年宿主中观察到的CD8+ T细胞损伤 肺直接离体和同性移植。 10倍多组学将阐明与年龄相关的表观遗传变化 在CD8+ T细胞中，同性移植将使年轻的CD8+ T细胞转移到老年宿主中，反之亦然 确定CD8+ T细胞是否是原发性免疫细胞，导致免疫反应受损（即 体重减轻，临床严重程度增加，病毒清除率延迟）。在AIM 2中，我将调查外部原因 CD8+ T细胞损伤，即肺泡巨噬细胞（AMS）。我将使用21色的多光谱流 细胞仪面板以枚举老年宿主中的M1和M2巨噬细胞种群。体外共培养和 AMS和CD8+ T细胞的Transwell分析将确定AMS是否直接损害CD8+ T细胞。选择性耗竭 老年小鼠的AM和年轻巨噬细胞的收养转移将决定AM如何贡献 老年宿主的免疫反应受损。在此目的中，还将执行10倍多组学 与年龄相关的表观遗传变化可能导致其异常M2积累的AM，我拥有的 在我的初步数据中也观察到。 该建议旨在了解老年宿主对HMPV的机理差异， 这将有助于阐明为什么老年人的HMPV感染更为严重。这些研究有可能 转化为临床环境，并为HMPV感染的更好管理和治疗做出贡献， 作为免疫调节。确定老年宿主中的分子靶标将指导安全和 所有高危人群的有效疫苗针对HMPV。 此外，该提议有巨大的培训机会，为我的职业目标做出了贡献 成为免疫学和传染病的临床医生和独立首席研究员。