Systems Immunology profiling of respiratory viral infections in vulnerable populations

易感人群呼吸道病毒感染的系统免疫学分析

• 批准号: 10420943
• 负责人: Matthew C. Altman
• 金额: $ 228.39万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-29 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420943
• 关键词: 2019-nCoV; Acute; Adenoviruses; Adult; Affect; Antibodies; Antigens; Asthma; Atlases; Autoimmune Diseases; Biological Assay; Biology; Blood; Blood specimen; COVID-19 pandemic; Cells; Characteristics; Child; Childhood; Chronic; Chronic Disease; Clinical; Coronavirus; Cytometry; Data; Data Analyses; Disease; Economics; Epidemic; Epithelial; Ethnic Origin; Etiology; Family; Flow Cytometry; Frequencies; Funding; Future; Generations; Genetic; Genomics; Goals; Human; Hypersensitivity; Immune; Immune System Diseases; Immune response; Immunology; Immunophenotyping; Immunosuppression; Individual; Infection; Inflammatory; Intervention; Kinetics; Lead; Measurement; Medical; Meta-Analysis; Metapneumovirus; Methods; Methylation; Modeling; Molecular; Morbidity - disease rate; Mucositis; Mucous Membrane; Multiomic Data; Obesity; Outcome; Pathogenesis; Patients; Pediatric cohort; Persons; Phenotype; Proteome; Race; Research; Respiratory Mucosa; Respiratory System; Respiratory Tract Infections; Respiratory syncytial virus; Rheumatoid Arthritis; Rhinovirus; Risk; Sampling; Severities; Severity of illness; Socioeconomic Status; Stimulus; System; Systems Biology; Therapeutic; United States National Institutes of Health; Vaccines; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Vulnerable Populations; atopy; base; benefit sharing; chronic inflammatory disease; clinical risk; cohort; comorbidity; experience; high dimensionality; human disease; in silico; infection risk; influenzavirus; insight; mathematical model; methylome; mortality; multidimensional data; multiple omics; novel; novel therapeutics; parainfluenza virus; pathogen; predict clinical outcome; programs; proteogenomics; respiratory infection virus; respiratory virus; response; sample collection; spatiotemporal; therapeutically effective; transcriptome; transmission process; treatment strategy; virus host interaction

SUMMARY/ABSTRACT – OVERALL Acute respiratory viral infections (ARVI) are the most frequently occurring global illness producing significant morbidity and mortality, particularly in vulnerable populations. Children suffer higher frequencies of ARVI and often experience re-infections. Common chronic diseases of childhood, most notably asthma but also allergies (atopy) and obesity, can predispose to increased severity of ARVI. Similarly, adults with chronic inflammatory diseases or on immunosuppression suffer significant consequences from ARVI. Adults with rheumatoid arthritis (RA) have an increased risk for infection and respiratory mucosal inflammation may contribute to autoimmune disease severity. The goal of this research program is to understand the molecular and cellular immune signatures of the vulnerable host response to ARVI to identify novel therapies and individuals at risk for clinical complications. The program includes a detailed systems immunology assessment of acute and long-term airway and adaptive systemic immune responses to naturally occurring ARVI. The first project will identify how asthma, atopy, and obesity lead to maladaptive immune responses to ARVI in pediatric subjects. The second project will examine host response to ARVI in adults with RA. RA is a disease provoked by environmental stimuli like respiratory infections and RA patients have baseline immune differences. These projects are complementary and synergistic by utilizing similar sample types and timing of sample collection, and common clinical endpoints. The individual projects benefit from shared multi-omics approaches through a Genomics Core for the sample processing and generation of airway host transcriptome, proteome, epithelial methylation, and viral quantity and expression data, along with host genetics. There is also a shared Adaptive Phenotyping Core for the generation of high dimensional cytometry data to broadly characterize immune cell phenotypes and for detailed identification of antigen-specific cells. This will allow for direct comparisons to be made between the adult and pediatric cohorts to identify common and divergent responses to ARVI. In the Overall, the first Specific Aim is to determine similar and divergent host responses to ARVI considering the pediatric allergy/asthma (Project 1) and adult RA (Project 2) cohorts. The second Specific Aim is to consider these host responses in the context of other large publicly-funded studies of viral infection through meta-analyses. The final Specific Aim will be to develop predictive spatiotemporal models of how mucosal and systemic immune responses to ARVI influence clinical outcomes. Our research program will produce novel mechanistic insights into the diversity and commonality of human immune responses to acute respiratory viruses and use cutting- edge methods to identify potential therapies.

摘要/摘要——总体 急性呼吸道病毒感染 (ARVI) 是最常发生的全球疾病，可产生重大影响 发病率和死亡率，特别是在弱势群体中，儿童遭受 ARVI 和 经常经历儿童期常见慢性疾病的再次感染，最明显的是哮喘，还有过敏。 （特应性）和肥胖可能会导致 ARVI 严重程度增加，同样，患有慢性炎症的成年人也会增加 ARVI 的严重程度。 患有类风湿性关节炎的成人会遭受严重的 ARVI 后果。 （RA）感染风险增加，呼吸道粘膜炎症可能导致自身免疫 该研究计划的目标是了解分子和细胞免疫系统。 脆弱宿主对 ARVI 反应的特征，以识别新疗法和面临临床风险的个体 该计划包括对急性和长期并发症的详细系统免疫学评估。 第一个项目将确定如何对自然发生的 ARVI 做出气道和适应性系统免疫反应。 哮喘、特应性和肥胖会导致儿科受试者对 ARVI 产生适应不良的免疫反应。 该项目将检查成人 RA 患者对 ARVI 的反应，RA 是一种由环境引起的疾病。 呼吸道感染和 RA 患者等刺激因素存在基线免疫差异。 通过利用相似的样本类型和样本采集时间来实现互补和协同，以及共同点 各个项目受益于基因组学的共享多组学方法。 用于样本处理和生成气道宿主转录组、蛋白质组、上皮甲基化、 病毒数量和表达数据以及宿主遗传学还有共享的适应性表型。 生成高维细胞计数数据以广泛表征免疫细胞表型的核心 以及抗原特异性细胞的详细鉴定，这将允许进行直接比较。 在成人和儿童队列之间进行比较，以确定对 ARVI 的常见和不同反应。 第一个具体目标是考虑到儿科疾病，确定宿主对 ARVI 的相似和不同的反应 过敏/哮喘（项目 1）和成人 RA（项目 2）队列 第二个具体目标是考虑这些宿主。 通过荟萃分析，在其他大型公共资助的病毒感染研究的背景下做出反应。 最终的具体目标将是开发粘膜和系统免疫如何预测的时空模型 对 ARVI 的反应会影响临床结果。 研究人类对急性呼吸道病毒的免疫反应的多样性和共性，并使用切割 边缘方法来识别潜在的疗法。