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: 10396593
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396593
• 关键词: Acute; Acute respiratory infection; Address; Antigens; Appearance; B-Lymphocytes; Biological Markers; Cancer Patient; Categories; Category B pathogen; Category C pathogen; Cell Culture Techniques; Cell Line; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Child; Chronic; Chronic Disease; Clinical; Clinical Trials; Communities; Databases; Development; Diagnosis; Disease; Double-Blind Method; Ecology; Elderly; Epidemic; Epidemiology; Epithelial; 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 System; 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; base; 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 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.

项目摘要 人类诺如病毒（Hunov），一种niaid B类病原体，是全球急性胃肠炎的主要原因， C类病原体和呼吸道合胞病毒（RSV）是全球主要的呼吸道病原体 孩子们。 Hunov感染导致​​所有年龄段的急性发病率显着，慢性病 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，并显着贡献 免疫功能低下的疾病和死亡，患有合并症和老年人的疾病。疾病负担 这些粘膜病原体的经济影响激发了疫苗开发的广泛努力。 两种病原体的未来5年预计疫苗，此预先许可窗口以及我们 最近使用干细胞衍生的人肠道的成功耕种系统开发了成功的耕种系统 类器官（HIO）和人类肺类器官RSV感染的最新描述（HLOS）提供了理想 将分析基因组学和功能研究应用于相关的人类培养系统的窗口来解决关键 有关Hunov和RSV多样性，进化和毒力的问题。我们提出的研究谨慎使用 选定涵盖Hunov和RSV疾病范围的临床标本，包括：（i）急性胃肠炎 在来自两个人群（美国和香港）的免疫能力儿童中，（ii）急性呼吸道感染 CDC中的儿童赞助了新的疫苗监视网络，（iii）良好控制的志愿者Hunov 挑战研究，（iv）慢性饥饿感染或急性RSV的移植和免疫功能低下的患者 感染，（v）Nitazoxanide（NTZ）治疗慢性Hunov的首次随机双盲临床试验 在移植接受者以及（vi）妇女和婴儿的第一阶段III试验中，RSV-F疫苗（Novavax）在 健康的孕妇预防婴儿疾病。除了以病原体为靶向的测序外，我们 将使用高吞吐量，集成的测序评估生态位生态位在病毒发病机理中的作用 介绍临床样品的细菌组和病毒蛋白的方法。全长（FL）基因组分析 HIS的Hunov和功能研究将提供有关不同人群病毒多样性的关键信息 随着时间的流逝，在不同的宿主中，存在型内型和基因型重组者的存在，以及 具有对NTZ耐药性的突变体的出现。 RSV和功能研究的FL基因组分析 HLOS和其他细胞系将建立RSV疾病严重程度的特定病毒特征，使您能够理解 免疫压力和免疫疗法对病毒基因组（包括抗原位点特异性）的影响 基序，以及B和T细胞表位的变化。科学界将受益于大型 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 在疫苗之前，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开发治疗疗法。