Viral Diversity and Pathogenicity in Mucosal Respiratory and Gastrointestinal Disease

粘膜呼吸系统和胃肠道疾病的病毒多样性和致病性

• 批准号: 10601131
• 负责人: Mary Kolb Estes
• 金额: $ 55.71万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601131
• 关键词: Acute; Acute respiratory infection; Address; Antigens; Appearance; B-Lymphocytes; Blood; Cancer Patient; Categories; Category B pathogen; Category C pathogen; Cell Culture Techniques; Cell Line; Cells; Cessation of life; Characteristics; Child; Chronic; Chronic Disease; Clinical; Clinical Trials; Communities; Databases; Development; Diagnosis; Disease; Double-Blind Method; Ecology; Elderly; Epidemic; Epidemiology; Epithelium; Evaluation; Evolution; Frequencies; Gastroenteritis; Gastrointestinal Diseases; Gene Expression Profile; Genetic; Genetic Recombination; Genetic Transcription; Genome; Genomics; Hong Kong; Human; Human Volunteers; Immune; Immune response; Immunocompetent; Immunocompromised Host; Immunologics; Immunotherapeutic agent; In Vitro; Individual; Infant; Infection; Integration Host Factors; Intestines; Knowledge; Lead; Length; Licensure; Lower respiratory tract structure; Lung; Metagenomics; Morbidity - disease rate; Mucous Membrane; National Institute of Allergy and Infectious Disease; Norovirus; Organoids; Pathogenesis; Pathogenicity; Patients; Performance; Physiological; Pluripotent Stem Cells; Population; Predisposition; Pregnant Women; Prevention; Randomized; Recombinants; Respiratory Disease; Respiratory Mucosa; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Severity of illness; Site; Specimen; System; T-Lymphocyte Epitopes; Testing; Therapeutic; Time; Transplant Recipients; Vaccines; Viral; Viral Genome; Viral Pathogenesis; Virulence; Virus; Virus Diseases; Virus Replication; Woman; age group; aging population; bacteriome; biomarker identification; burden of illness; clinical development; clinically relevant; comorbidity; economic impact; epidemiologic data; falls; gastrointestinal; genetic signature; genomic data; genomic signature; human morbidity; human mortality; improved; insight; metagenomic sequencing; microbial; mortality; mutant; nitazoxanide; novel; novel vaccines; pandemic disease; pathogen; patient subsets; phase III trial; preclinical development; pressure; prevent; reconstitution; respiratory; respiratory pathogen; response; stem cells; surveillance network; targeted sequencing; therapeutic development; therapy resistant; tool; vaccine development; viral genomics; virome; virus host interaction

PROJECT SUMMARY Human norovirus (HuNoV), a NIAID Category B pathogen, is the leading cause of acute gastroenteritis globally, and respiratory syncytial virus (RSV), a Category C pathogen, is the major global respiratory pathogen of children. HuNoV infections result in significant acute morbidity in all age groups, chronic disease in immunocompromised cancer and transplant patients, and death in young children and older adults. RSV is the leading cause of lower respiratory tract morbidity and mortality among children, and contributes significantly to illness and death in the immunocompromised, those with co-morbidities and older adults. The burden of disease and economic impact of these mucosal pathogens have stimulated extensive efforts for vaccine development. With vaccines anticipated in the next 5 years for both pathogens, this pre-licensure window, together with our recent development of a successful cultivation system for HuNoVs using stem cell-derived human intestinal organoids (HIOs) and the recent description of RSV infections in human lung organoids (HLOs) provide an ideal window to apply analytical genomics and functional studies in relevant human culture systems to address key questions about HuNoV and RSV diversity, evolution and virulence. Our proposed studies utilize carefully selected clinical specimens covering the spectrum of HuNoV and RSV illness, including: (i) acute gastroenteritis in immunocompetent children from two populations (USA and Hong Kong), (ii) acute respiratory infections in children in the CDC sponsored New Vaccine Surveillance Network, (iii) well-controlled volunteer HuNoV challenge studies, (iv) transplant and immunocompromised patients with chronic HuNoV infection or acute RSV infection, (v) the first randomized double-blind clinical trial of nitazoxanide (NTZ) for treatment of chronic HuNoV in transplant recipients, and (vi) women and infants in the first phase III trial of an RSV-F vaccine (Novavax) in healthy pregnant women for preventing disease in their infants. In addition to pathogen-targeted sequencing, we will evaluate the role of the ecological niche in viral pathogenesis using high throughput, integrated sequencing approaches to profile the bacteriome and virome of clinical samples. Full-length (FL) genomic analyses of HuNoV and functional studies in HIEs will provide critical information on virus diversity in different populations and over time in diverse hosts, the presence of intragenotypic and intergenotypic recombinants, and the appearance of mutants with treatment resistance to NTZ. FL genomic analyses of RSV and functional studies in HLOs and other cell lines will establish specific viral signatures of RSV disease severity, enable understanding the effects of immune pressure and immunotherapeutics on the viral genome including antigenic site specific motifs, and changes in B and T cell epitopes. The scientific community will benefit immensely from large databases of FL genomes for HuNoV and RSV, and functional studies in novel human cultures that comprehensively address viral genomic signatures, microbial ecology and host responses before vaccine introduction. Identifying biomarkers, viral and host targets will guide treatment and development of therapeutics.

项目概要 人类诺如病毒 (HuNoV) 是 NIAID B 类病原体，是全球急性胃肠炎的主要原因， 呼吸道合胞病毒（RSV）是C类病原体，是全球主要的呼吸道病原体 孩子们。 HuNoV 感染导致所有年龄段的患者出现显着的急性发病率， 免疫功能低下的癌症和移植患者，以及幼儿和老年人的死亡。 RSV 是 儿童下呼吸道发病率和死亡率的主要原因，并在很大程度上导致 免疫功能低下者、患有合并症的人和老年人的疾病和死亡。疾病负担 这些粘膜病原体的经济影响刺激了疫苗开发的广泛努力。 预计未来 5 年内将推出针对这两种病原体的疫苗，这个预许可窗口以及我们的 最近利用干细胞衍生的人类肠道成功开发了 HuNoV 培养系统 类器官 (HIO) 和最近对人肺类器官 (HLO) 中 RSV 感染的描述提供了理想的 在相关人类文化系统中应用分析基因组学和功能研究以解决关键问题的窗口 有关 HuNoV 和 RSV 多样性、进化和毒力的问题。我们提出的研究仔细利用 选定的临床标本涵盖 HuNoV 和 RSV 疾病谱，包括： (i) 急性胃肠炎 来自两个人群（美国和香港）的免疫功能正常的儿童，(ii) 急性呼吸道感染 CDC 赞助的新疫苗监测网络中的儿童，(iii) 控制良好的志愿者 HuNoV 挑战研究，(iv) 患有慢性 HuNoV 感染或急性 RSV 的移植和免疫功能低下患者 (v) 硝唑尼特 (NTZ) 治疗慢性 HuNoV 的首个随机双盲临床试验 (vi) 接受 RSV-F 疫苗 (Novavax) 的第一个 III 期试验中的妇女和婴儿 健康孕妇预防婴儿疾病。除了病原体靶向测序之外，我们 将使用高通量、集成测序来评估生态位在病毒发病机制中的作用 分析临床样本的细菌组和病毒组的方法。全长（FL）基因组分析 HuNoV 和 HIE 的功能研究将提供有关不同人群中病毒多样性的关键信息 随着时间的推移，在不同的宿主中，基因型内和基因间重组体的存在，以及 对 NTZ 治疗具有抗性的突变体的出现。 RSV 的 FL 基因组分析和功能研究 HLO 和其他细胞系将建立 RSV 疾病严重程度的特定病毒特征，使人们能够了解 免疫压力和免疫治疗对病毒基因组的影响，包括抗原位点特异性 基序以及 B 和 T 细胞表位的变化。科学界将从大量的研究中受益匪浅 HuNoV 和 RSV 的 FL 基因组数据库，以及新型人类文化中的功能研究 疫苗接种前全面解决病毒基因组特征、微生物生态学和宿主反应 介绍。识别生物标志物、病毒和宿主靶标将指导治疗和疗法的开发。