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; 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）是最常见的全球疾病，产生明显的明显 发病率和死亡率，尤其是在弱势群体中。儿童遭受较高的Arvi频率和 经常经历重新感染。童年的常见慢性疾病，最著名的是哮喘，但也是过敏 （特应性）和肥胖，可能会增加Arvi的严重程度。同样，患有慢性炎症的成年人 疾病或免疫抑制受到ARVI的重大影响。类风湿关节炎的成年人 （RA）感染和呼吸粘膜注射的风险增加可能导致自身免疫性 疾病的严重程度。该研究计划的目的是了解分子和细胞免疫 弱势宿主对ARVI的签名，以识别有临床风险的新型疗法和个人 并发症。该计划包括对急性和长期的详细系统免疫学评估 气道和适应性的全身免疫反应对天然发生的ARVI。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的ARVI导致不良适应性免疫回报。第二个 项目将检查RA成年人对ARVI的宿主反应。 RA是一种由环境引起的疾病 刺激如呼吸道感染和RA患者具有基线免疫差异。这些项目是 完全且通过使用类似的样本类型和样本收集的时间来协同和协同作用， 临床终点。单个项目通过基因组学从共享的多摩学方法中受益 气道宿主转录组，蛋白质组，上皮甲基化的样品处理和生成的核心， 以及病毒量和表达数据以及宿主遗传学。也有共同的自适应表型 产生高维细胞仪数据的核心，以广泛表征免疫球表型 并详细识别抗原特异性细胞。这将允许进行直接比较 在成年人和小儿同伙之间，以确定对Arvi的常见和不同的反应。总体上 第一个具体目的是确定考虑小儿的类似宿主对Arvi的反应 过敏/哮喘（项目1）和成人RA（项目2）队列。第二个具体目的是考虑这些主机 通过荟萃分析的其他大型公共资助的病毒感染研究的反应。 最终的具体目的是开发粘膜和全身免疫的预测时空模型 对ARVI的反应会影响临床结果。我们的研究计划将产生新颖的机械见解 对人类免疫调查的多样性和共同点对急性呼吸道病毒的多样性和共同点，并使用效果 - 识别潜在疗法的边缘方法。