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.

总结/摘要-总体 急性呼吸道病毒感染（阿尔维）是最常见的全球性疾病， 发病率和死亡率，特别是在弱势群体中。儿童患阿尔维流感的频率较高， 经常会再次感染。常见的儿童慢性疾病，最明显的是哮喘，但也过敏 （特应性）和肥胖，可倾向于增加阿尔维的严重性。同样，患有慢性炎症的成年人 疾病或免疫抑制遭受阿尔维的严重后果。类风湿性关节炎患者 (RA)感染的风险增加，呼吸道粘膜炎症可能导致自身免疫性疾病。 疾病严重程度。这项研究计划的目标是了解分子和细胞免疫 易感宿主对阿尔维的应答特征，以确定新的治疗方法和临床风险个体。 并发症该计划包括一个详细的系统免疫学评估的急性和长期 对自然发生的阿尔维的气道和适应性全身免疫应答。第一个项目将确定如何 哮喘、特应性和肥胖导致儿科受试者对阿尔维的适应不良免疫应答。第二 该项目将检查成人RA患者对阿尔维疫苗的反应。RA是一种由环境因素引起的疾病， 刺激如呼吸道感染和RA患者具有基线免疫差异。这些项目 通过利用相似的样本类型和样本收集时间， 临床终点。单个项目通过基因组学共享多组学方法受益 用于样本处理和气道宿主转录组、蛋白质组、上皮甲基化的生成的核心， 以及病毒数量和表达数据，沿着宿主遗传学。还有一个共同的适应性表型 用于生成高维细胞计数数据以广泛表征免疫细胞表型的核心 并用于抗原特异性细胞的详细鉴定。这将允许进行直接比较 成人和儿童队列之间的差异，以确定对阿尔维的共同和不同反应。总的来说， 第一个具体目标是确定考虑到儿童对阿尔维的相似和不同的宿主反应， 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主机 在其他大型公共资助的病毒感染研究的背景下，通过荟萃分析的反应。的 最后的具体目标将是开发预测性时空模型， 对阿尔维的反应影响临床结果。我们的研究计划将产生新的机械见解 人类对急性呼吸道病毒的免疫反应的多样性和共同性， 边缘方法来识别潜在的疗法。